Blood Journal
Leading the way in experimental and clinical research in hematology

Phase II and pharmacodynamic study of oral forodesine in patients with advanced and/or fludarabine-treated chronic lymphocytic leukemia

  1. Kumudha Balakrishnan1,
  2. Dushyant Verma2,
  3. Susan O'Brien2,
  4. John Michael Kilpatrick3,
  5. Yuling Chen1,
  6. Brenita F. Tyler1,
  7. Susan Bickel2,
  8. Shanta Bantia3,
  9. Michael J. Keating2,
  10. Hagop Kantarjian2,
  11. Varsha Gandhi1,*, and
  12. Farhad Ravandi2
  1. 1 Department of Experimental Therapeutics, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, United States;
  2. 2 Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, United States;
  3. 3 BioCryst Pharmaceuticals Inc, Birmingham, AL, United States
  1. * Corresponding author; email: vgandhi{at}


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 as NCT00289549.

  • Submitted February 26, 2010.
  • Accepted March 31, 2010.