Gefitinib as a Potential Treatment for Aggressive CLL

Abstract

Chronic lymphocytic leukemia (CLL) is presently an incurable disease that is expected to increase in prevalence, as a result of the aging population. Currently, the standard treatment used is chlorambucil or fludarabine, combined with cyclophosphamide and rituximab. The disease has a variable course. Recently, it has been shown that the expression of the tyrosine kinase, ZAP-70 in CLL is a strong indicator of poor prognosis, with a greatly reduce time to treatment from diagnosis, compared with ZAP-70 negative patients. Therefore, therapy that specifically targets ZAP-70 positive CLL might improve these patients’ outcomes. The tyrosine kinase inhibitor gefitinib has been shown to reduce the phosphorylation levels of several tyrosine kinases including ZAP-70 and SYK. We treated several ZAP-70 positive and ZAP-70 negative patient samples with gefitinib and found that gefitinib had a much lower IC 50 for ZAP-70 positive patients than it did for ZAP-70 negative patients. Also, gefitinib induced more apoptosis in the ZAP-70 positive cell line Jurkat than it did in cells lines not expressing ZAP-70. These results support a role for gefitinib in the treatment of ZAP-70 positive CLL.