PS1083 EFFICACY AND TOXICITY OF INTENSIVE CHEMOTHERAPY REGIMENS IN PRIMARY MEDIASTINAL (THYMIC) LARGE B-CELL LYMPHOMA
Authors: I. Zavodnova, G. Tumyan, O. Trofimova, M. Kichigina
Journal: HemaSphere (2019)

Background: The SAM domain and HD domain 1 (SAMHD1) protein is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase, which has been initially described to restrict human immunodeficiency virus type 1 (HIV-1) in the immune cells through depletion of intracellular dNTP substrates required for HIV-1 replication. Mutations of SAMHD1 gene have been linked to Aicardi-Goutières syndrome (AGS) and have been detected in a subset of chronic lymphocytic leukemia resulting in decreased SAMHD1 mRNA and protein levels and also in 20% of T-prolymphocytic leukemias. Therefore, SAMHD1 may play a role in oncogenesis as a tumor suppressor. In addition, SAMHD1 may confer resistance to nucleoside-based chemotherapies such as cytarabine in acute myeloid leukemia (Herold et al, Nat Med 2017; 23(2):256–263). The clinical significance of SAMHD1 in of diffuse large B- cell lymphoma (DLBCL) is not yet known. Aims: To investigate the expression of SAMHD1 and its associations with clinicopathologic parameters and clinical outcome in diffuse large B-cell lymphoma (DLBCL). Methods: The patient cohort included 112 cases of de novo DLBCL diagnosed and treated with R-CHOP regimen at Karolinska University Hospital (Sweden). In addition, 4 reactive lymph nodes and 2 reactive tonsils were included in the study for comparison. SAMHD1 expression was assessed by immunohistochemistry performed on tissue microarrays with duplicate tumor cores from each case or on full tissue sections. All tissue specimens were diagnostic biopsies obtained prior to treatment. A double immunostaining (SAMHD1/CD68) assay was utilized as previously described (Rassidakis et al, Blood Cancer J, 2018; 8:98) since CD68+ histiocytes are strongly positive for SAMHD1 and should be distinguished from the lymphoma cells. The percentage of SAMHD1-positive cells was calculated by counting at least 500 tumor cells in each case. Overall survival (OS) and event-free survival (EFS) were the clinical outcome endpoints. Survival analyses were performed using the Kaplan-Meier method (log-rank test) and Cox regression models. The statistical correlations between SAMHD1 as a continuous variable (% of positive lymphoma cells) and other parameters were performed using the Spearman R correlation coefficient, Mann-Whitney U and Kruskal-Wallis tests. Results: In reactive lymph nodes and tonsils, strong SAMHD1 expression was observed in histiocytes and reactive small T-lymphocytes, whereas much weaker expression was seen in a subset of germinal center B-cells. The majority of small B-lymphocytes were negative. SAMHD1 was expressed in 60 / 112 (53.6%) DLBCL at a variable level with the percentage of SAMHD1 positive tumor cells ranging from 5 to 100%. The staining intensity was generally weaker than that of histiocytes with the exception of 3 / 60 DLBCLs that showed equally strong intensity. The percentage of SAMHD1+ lymphoma cells was significantly higher in DLBCL with germinal center (GC) phenotype (p = 0.02), and positively correlated with expression of MYC (p = 0.009) and CD30 (P = 0.04), as well as with tumor cell proliferation (p = 0.03). In multivariate survival analysis, the percentage of SAMHD1+ neoplastic cells was independently associated with inferior EFS (p = 0.038) along with patient age and LDH level at presentation. Summary/Conclusion: SAMHD1 is expressed in approximately half of de novo DLBCLs at a variable level and correlates with cell of origin (GC), biomarkers of tumor aggressiveness (eg MYC, proliferation) and clinical outcome.