The effects of sildenafil citrate on malignant B-cells in patients with chronic lymphocytic leukemia

Abstract

7076 Background: Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western Hemisphere, with over 10,000 cases diagnosed annually in the United States. It is characterized by progressive accumulation of functionally incompetent long-lived lymphocytes, shown to be secondary to a defect in programmed cell death or apoptosis. The phosphodiesterase inhibitor sildenafil induces capsase dependent apoptosis of malignant B lymphocytes in vitro. This study will test the hypothesis that sildenafil reduces the expression of BCL-2 and increases the spontaneous apoptosis rate of malignant B-cells in patients with CLL. Methods: Thirteen patients with Rai Stage 0 CLL were enrolled. Nine of the patients were aged sixty-five years or older and received sildenafil 25 mg weekly; four patients were under the age of sixty-five and received sildenafil 25 mg weekly. All patients took the medication for a total of three months. Lymphocyte counts, BCL-2 expression, caspase 3 activity, and apoptosis rate were monitored on enrollment and monthly for duration of the study. Results: The median age of patients enrolled in the study was 74 with a median white blood cell count of 18 x103/mL. Twelve of the 13 patients completed three months of therapy. While one patient withdrew due to blehparitis, not felt to be a side effect of sildenafil, all other patients tolerated the medication well without any adverse effects. There was no significant decrease in white blood cell count or Bcl-2 expression; capsase 3 activity and apoptosis rates remained undetectable on presentation and throughout treatment. Conclusions: At a dose of 25 to 50 mg weekly, sildenafil does not appear to have any effects on the malignant B cells in CLL. While this dose may not produce a measurable clinical or cellular response, higher doses may still have an effect on the malignant B cells of CLL. The dose of sildenafil was based on a case series of patients with Viagra who had decreases in IgM levels while taking sildenafil 25–50 mg weekly. Subsequent studies in have shown a greater reduction in IgM in patients taking sildenafil 100 mg daily and patients did not report any significant side effects. A follow-up study using sildenafil 100 mg daily is warranted. No significant financial relationships to disclose.