Ferenc Takács1, Gábor Mikala2, Noémi Nagy1, Andrea Reszegi1, Ágnes Czeti1, Gábor Szalóki1, Gábor Barna1. 1. 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary. 2. South-Pest Central Hospital - National Institute for Hematology and Infectious Diseases, Department of Hematology and Stem Cell Transplantation, Budapest, Hungary.
Abstract
BACKGROUND: The Bcl-2 inhibitor venetoclax has been recently introduced into the treatment of chronic lymphocytic leukemia. Venetoclax is a highly effective drug, however acquired resistance may make long-term treatment challenging. In our study, we present potential novel resistance mechanisms and prognostic markers that are potentially able to predict the early appearance of the resistance. MATERIAL AND METHODS: Repeated complete blood counts, flow cytometric measurements, and physical examinations were performed during the patient follow-up. Clinical and laboratory parameters showed that the patient developed clinical resistance to venetoclax on day 450 of therapy. Resistance mutation analysis (D103Y) and apoptosis arrays from samples at the time of resistance were done. RESULTS: We were able to identify the resistance mutations just a very low variant allele frequency level from the resistant samples. Furthermore we detected increased Bcl-2 expression in peripheral blood (PB), and XIAP overexpression in bone marrow (BM) that could lead to venetoclax resistance. We examined the immunophenotype of CLL cells and recognized that while the expression of CD86 did not change until day 270 of the treatment, since then its expression steadily increased. Moreover, we compared the expression of CD86 in the resistant PB and BM samples and did not find a notable difference between the compartments. CONCLUSION: Our results imply that CLL cells may try to avoid the apoptotic effect of venetoclax through increased CD86 expression by activating antiapoptotic mechanisms. Confirmatory experiments are still required to unequivocally prove that CD86 is a prognostic marker, however, its predictive property during the venetoclax treatment is promising.
BACKGROUND: The Bcl-2 inhibitor venetoclax has been recently introduced into the treatment of chronic lymphocytic leukemia. Venetoclax is a highly effective drug, however acquired resistance may make long-term treatment challenging. In our study, we present potential novel resistance mechanisms and prognostic markers that are potentially able to predict the early appearance of the resistance. MATERIAL AND METHODS: Repeated complete blood counts, flow cytometric measurements, and physical examinations were performed during the patient follow-up. Clinical and laboratory parameters showed that the patient developed clinical resistance to venetoclax on day 450 of therapy. Resistance mutation analysis (D103Y) and apoptosis arrays from samples at the time of resistance were done. RESULTS: We were able to identify the resistance mutations just a very low variant allele frequency level from the resistant samples. Furthermore we detected increased Bcl-2 expression in peripheral blood (PB), and XIAP overexpression in bone marrow (BM) that could lead to venetoclax resistance. We examined the immunophenotype of CLL cells and recognized that while the expression of CD86 did not change until day 270 of the treatment, since then its expression steadily increased. Moreover, we compared the expression of CD86 in the resistant PB and BM samples and did not find a notable difference between the compartments. CONCLUSION: Our results imply that CLL cells may try to avoid the apoptotic effect of venetoclax through increased CD86 expression by activating antiapoptotic mechanisms. Confirmatory experiments are still required to unequivocally prove that CD86 is a prognostic marker, however, its predictive property during the venetoclax treatment is promising.
Entities:
Keywords:
Chronic lymphocytic leukemia; drug resistance; flow cytometry; targeted therapy
Authors: Ferenc Takács; Lili Kotmayer; Ágnes Czeti; Gábor Szalóki; Tamás László; Gábor Mikala; Ágnes Márk; András Masszi; Péter Farkas; Márk Plander; Júlia Weisinger; Judit Demeter; Sándor Fekete; László Szerafin; Beáta Margit Deák; Erika Szaleczky; Adrienn Sulák; Zita Borbényi; Gábor Barna Journal: Pathol Oncol Res Date: 2022-09-21 Impact factor: 2.874