A Novel Combination Therapy Based On the Genetics of Follicular Lymphoma

Abstract 1330

Follicular lymphoma (FL) is a common and incurable form of Non-Hodgkin's lymphoma characterized by the translocation t(14;18) that results in increased expression of the anti-apoptotic BCL2 protein. Exactly what drives expansion of the malignant B-cells in FL is not clear. Here we report recurrent genetic lesions targeting cell cycle controls in FL. These include mutations in the CYCLIN D3 gene (6%), chromosomal gains of CDK4 (31%), and losses of CDKN2a/b (9%), and RB1 (10%). Consistent with the genetic data, 46% of FLs show abundant RB phosphorylation, and together these lesions identify patients with advanced tumours who fare badly with standard therapies. In a murine FL model loss of cell cycle control acts as an oncogenic driver and cooperates with BCL2. Moreover, xenografted FLs respond to CDK4/6 inhibition and combinations with BH3 mimetic drugs cause extensive apoptosis and consolidate the therapeutic effect. Hence, loss of cell cycle control is an oncogenic event in ∼50% of FL and the simultaneous blockade of CDK4 and BCL2 is an effective combination therapy for FL.