Persistent lymphocytes are not addicted to a single signaling pathway. To determine whether persistent lymphocytes were dependent on a single signaling pathway for survival, cells at baseline and 9 months from patients with persistent lymphocytosis were treated with various inhibitors of the BCR signaling pathway. AEB-071 was dosed at 1 μM, Dasatinib at 5 μM, MK2206 at 1 μM, IPI-145 at 1 μM, CI-1040 at 1 μM, and Dinaciclib at 1 μM. Dinaciclib was washed out at 2 hours. Annexin V/propidium iodide staining and flow cytometry were used to identify viable cells (Annexin negative/PI negative) after 72 hours. No single drug produced more effective cytotoxicity at a late time point compared with baseline. Dinaciclib, a cyclin-dependent kinase inhibitor, induced robust cytotoxicity both at baseline and at 9 months of ibrutinib therapy.