November 4th 2004
Bcl-2 protein is upregulated in a wide variety of lymphoid malignancies,including chronic lymphocytic leukemia (CLL). The proteinis thought to be responsible for maintaining the viability of malignantlymphoid cells and may contribute to chemotherapy and radiotherapyresistance. Previous studies have shown that reduction of bcl-2 expressionby antisense therapy sensitizes cells to chemotherapy-inducedapoptosis. In vitro, the Bcl-2 antisense drug oblimersen sodium(Genasense, previously known as G3139) enhances the apoptotic responsein CLL cells to fludarabine (Fludara), corticosteroids,alemtuzumab (Campath), and rituximab (Rituxan). A phase I trial inpatients with refractory/relapsed CLL showed that patients with CLLwere more sensitive to oblimersen than patients with solid tumors. Themaximum tolerated oblimersen dose was 3 mg/kg/d, and the most commondose-limiting reaction was hypotension, frequently in associationwith high spiking fever. In this study, oblimersen displayed limited singleagentactivity, including tumor lysis syndrome, transient decreases incirculating CLL cells, and reduction of splenomegaly and size of lymphnodes. Major responses were observed in 9% of patients. Subsequently,a phase III trial evaluating fludarabine and cyclophosphamide with orwithout oblimersen (3 mg/kg/d for 7 days) was initiated in patients withrelapsed or refractory CLL. This trial recently completed accrual of241 patients.