Prognosis of patients with fludarabine-refractory CLL is poor and novel therapies are needed. Forodesine is a new and potent purine nucleoside phosphorylase inhibitor. CLL patients with primary resistance to fludarabine-based therapy or with progressive disease were eligible for oral forodesine (200mg/day) for up-to 24 weeks. Eight patients with median lymphocyte count 35.9x109/L and median serum β2 microglobulin 6.45 mg/L were treated. Six had Rai stage III-IV and were previously heavily treated (median prior therapy = five). Two had transient decrease in lymphocyte count to normal, while in five, disease progressed. Adverse events were mild. Steady-state level of forodesine ranged 200-1300 nM and did not reach desired 2 µM level. PNP inhibition ranged from 57 - 89% and steady-state dGuo concentration was median 1.8 µM. Intracellular dGTP increase was very modest; from median 6 µM to 10 µM. Compared to in vivo, in vitro incubations of CLL lymphocytes with 10 or 20 µM dGuo + forodesine (2 µM) resulted in accumulation of higher levels of dGTP (40 - 250 µM) which resulted in increase in apoptosis. Forodesine has biological activity and pharmacodynamic parameter suggests alternate dosing schedule and/or higher doses to achieve greater intracellular dGTP may be beneficial in this patient population. This study is registered at http://clinicaltrials.gov as NCT00289549.
- Submitted February 26, 2010.
- Accepted March 31, 2010.
- Copyright © 2005 American Society of Hematology