Abstract 5369: Low asparagine synthetase expression and in vitro sensitivity highlights L-asparaginase potential for the treatment of aggressive lymphomas (2015)

Abstract L-asparaginase (L-ASPA) is included in current chemotherapy regimen for the treatment of acute lymphoblastic leukemia (ALL). The sensitivity of ALL to L-ASPA has been linked to the incapacity of leukemic cells to produce their own asparagine, since they are deficient in a specific enzyme, asparagine synthetase (ASNS). Thus, ASNS-negative leukemic cells rely on plasmatic asparagine and can be starved to death by L-ASPA treatment. Several studies evidenced the potential of asparagine depletion to treat lymphomas. Indeed, L-ASPA is routinely administered to treat canine lymphomas and its adjunction in chemotherapy regimens significantly improves the outcome of patients with NK/T cell lymphoma. Some studies suggest its benefit for the treatment of B and T-cell non-Hodgkin lymphomas (NHL). In this study, we assessed the in vitro sensitivity to L-ASPA of 11 lymphoma cell lines, including diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma (PTCL) and other NHL cell lines. We analyzed ASNS expression in tissue microarrays and biopsies from 226 cases of lymphomas, including 158 DLBCL, 15 PTCL, as well as other NHL and Hodgkin lymphomas. Sensitivity to L-ASPA (expressed as an IC50) was assessed by measuring the cell viability in the presence of various concentrations of L-ASPA. ASNS expression was assessed with a validated immunohistochemistry method attributing a score based on labeling intensity from 0 (no expression) to 3 (strong expression). Tumors expressing no/low ASNS (scores 0 and 1) were considered potentially sensitive to asparagine depletion. All lymphoma cell lines were proved to be sensitive to L-ASPA. Their in vitro sensitivity usually exceeded well-known sensitive cell lines (MOLT-4 and HL-60) representative of acute leukemia. ASNS expression was null/low in 171/226 (76%) total cases of lymphomas. 118/158 (75%) DLBCL cases expressed no/low ASNS, whereas ASNS expression was low/null in 2/15 (13%) PTCL cases. Globally, B-cell NHL displayed a lower expression of ASNS than T-cell NHL, Hodgkin lymphoma and non tumoral lymph nodes. The in vitro sensitivity to L-ASPA of all lymphoma cell lines and the low/null expression of ASNS in the majority of the lymphoma tissues tested suggest that L-ASPA may be effective for the treatment of various lymphomas. As suggested by ASNS expression, L-ASPA treatment may be particularly effective in DLBCL and others B-cell NHL, whereas its efficacy in T-cell NHL is probably more limited. However, L-ASPA has only been used scarcely in the treatment of lymphomas despite promising clinical responses. Its well known serious side-effects (hypersensitivity, coagulation disorders, pancreatitis…) render its use particularly hazardous in older or frail patients. The development of a new formulation of L-ASPA with better safety profile must be considered in order to allow the clinical development of L-ASPA in the treatment of aggressive lymphomas. Citation Format: Willy Berlier, Karine Aguera, Fanny Gallix, Anne-Marie Chevrier, Alexandra Traverse-Glehen, Yann Godfrin. Low asparagine synthetase expression and in vitro sensitivity highlights L-asparaginase potential for the treatment of aggressive lymphomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5369. doi:10.1158/1538-7445.AM2015-5369