Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster II
Hematology Disease Topics & Pathways:
Research, Translational Research, Lymphomas, Non-Hodgkin lymphoma, CHIP, Diseases, Lymphoid Malignancies, Biological Processes, Study Population, Human
Methods: Whole exome sequencing (WES) derived from blood/PBMC from lymphoma patients with paired tumor samples was analyzed to identify CH-related myeloid drivers in 42 previously reported genes. We used Sention-Tnhaplotype2 somatic pipeline with a custom panel of normals from whole blood samples. To avoid tumor contamination, we filtered variants for which VAF in the tumor was higher than that in the germline sample. Other filtering criteria included HIGH/MODERATE impact; read count > 1 in both forward and reverse reads; gnomAD_AF < 0.01. We used the R “survival” package Cox regression implementation for outcome and other statistical analysis.
Results: Genomic and clinical data of 507 patients from MER-FL and 383 patients from MER-DLBCL cohorts, with median age of 60 and 64 respectively, were available for analysis. CH-related mutations were present in 17.16% (87/507) in FL and 18.28% (70/383) in DLBCL cohorts with a VAF cut off >2%. The most common CH-related mutations were DNMT3A (5%), CREBBP (2%), TET2 (1%), ASXL1 (1%) and PPM1D (1%) in MER-FL while DNMT3A (5%), TET2 (3%), TP53 (3%), ASXL1 (2%) and PPM1D (1%) in MER-DLBCL cohort. Both the prevalence of CH-related mutations and their average VAF increased with age, consistent with literature. Finally, cox regression analysis suggested that CH-related mutations were associated with significantly inferior overall survival (OS) in both FL and DLBCL cohorts (HR 1.6 p=0.028 and HR 2.3 p=<0.001 respectively); however only in DLBCL this association was significant after age correction (HR 1.8 p=0.008). When separated by individual gene mutations, genes of interest with inferior OS included TP53 (n=4, HR 3.1, p=0.057) in FL and PPM1D (n=3 HR 2.6 p=0.1), TP53 (n=8 HR 2.1 p=0.1) and DNMT3A (n=14, HR=2.0, p=0.048) in DLBCL; however, these estimates did not quite reach statistical significance.
Conclusions: Taken together, our exploratory analysis indicates that CH-related mutations associate with worse OS in lymphoma patients, supporting the rationale for evaluation of CH for the risk assessment in lymphoma. Furthermore, DLBCL displays of larger size effect, which may be related to different treatment regimes. Additional studies will be needed to elucidate the interaction between high dose chemotherapy regimes and CH-associated adverse events.
Disclosures: Lopez: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hasan: Bristol Myers Squibb: Current Employment. Huang: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Amzallag: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Suragani: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Gandhi: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Novak: Bristol Myers Squibb: Research Funding. Cerhan: Protagonist Therapeutics: Other: SMC; BMS: Research Funding; Genentech: Research Funding; GenMab: Research Funding. Hasan: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.
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