The ratio of cyclin D1/p21kip baseline gene expression and SPARC gene expression can be potential predictors of non-Hodgkin's lymphoma (NHL) patient response to lenalidomide therapy

Abstract

22150 Background: Lenalidomide (LEN) is approved for the treatment of transfusion-dependent patients with anemia due to low- or intermediate-1-risk MDS associated with a del 5q cytogenetic abnormality, and in combination with dexamethasone for the treatment of previously treated multiple myeloma patients. LEN also has activity in a variety of hematological malignancies and disorders, including amyloidosis, myelofibrosis, chronic lymphocyte leukemia, cutaneous T cell lymphoma and non-Hodgkin's lymphoma (NHL). To date, predictive markers and biomarkers of LEN response have not been reported. Methods: We have analyzed the expression of several important genes involved in cancer cell cycle, proliferation and angiogenesis using various NHL cell lines by quantitative real-time polymerase chain reaction, to identify patterns of constitutive gene expression that may predict sensitivity of NHL tumors, particularly mantle cell lymphoma (MCL), to LEN therapy. Results: We observed that the level of constitutive cyclin D1 gene expression in MCL cell lines correlates with the order of sensitivity to LEN: Rec-1> Jeko-1> Granta-519 > JVM-2. Conversely, the order of constitutive p21kip expression is: JVM-2 > Granta-519 > Jeko-1 > Rec-1, and thus constitutive p21kip gene expression is inversely proportional to LEN sensitivity. Therefore, the baseline cyclin D1 to p21kip gene expression ratio could be predictive of patient response to LEN therapy. We also found that LEN markedly increases SPARC (Osteonectin) gene expression in NHL cells in a manner that correlates with the anti-proliferative activity of LEN against that cell line. The order of sensitivity to LEN by various NHL cell lines is Namalwa (Burkitt's Lymphoma)>Rec-1>Jeko-1>Granta-519>JVM-2 (all MCL)> DB (Diffuse Large B Cell Lymphoma). Thus SPARC gene expression may be a biomarker of NHL or MCL tumor response to LEN. Conclusion: High baseline cyclin D1 and low p21kip gene expression in MCL cell lines correlates with sensitivity to LEN and may be predictive of a good clinical response to LEN. Furthermore, monitoring of SPARC expression in NHL or MCL patients may enable early identification of patients who are responding to LEN therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celgene Celgene