Phase 2 and pharmacodynamic study of oral forodesine in patients with advanced, fludarabine-treated chronic lymphocytic leukemia.
Forodesine is a new and potent purine nucleoside phosphorylase (PNP) inhibitor. Patients with chronic lymphocytic leukemia (CLL) with primary resistance to fludarabine-based therapy or with progressive disease were eligible for oral forodesine (200 mg/d) for up to 24 weeks. Eight patients with median lymphocyte count of 35.9 x 10(9)/L and median serum beta2 microglobulin level of 6.45 mg/L were treated. Six had Rai stage III to IV and were previously heavily treated (median prior therapy = 5). Two had transient decrease in lymphocyte count to normal, whereas in 5, disease progressed. Adverse events were mild. Steady-state level of forodesine ranged from 200 to 1300 nM and did not reach desired 2 microM level. PNP inhibition ranged from 57% to 89% and steady-state 2'-deoxyguanosine (dGuo) concentration median was 1.8 microM. Intracellular deoxyguanosine triphosphate (dGTP) increase was very modest, from median of 6 microM to 10 microM. Compared with in vivo, in vitro incubations of CLL lymphocytes with 10 or 20 microM dGuo and forodesine (2 microM) resulted in accumulation of higher levels of dGTP (40-250 microM) which resulted in increase in apoptosis. Forodesine has biologic activity in CLL; pharmacodynamic parameters suggest that an alternate dosing schedule and/or higher doses to achieve greater intracellular dGTP may be beneficial in this patient population.
Balakrishnan
Kumudha
K
Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Verma
Dushyant
D
O'Brien
Susan
S
Kilpatrick
John Michael
JM
Chen
Yuling
Y
Tyler
Brenita F
BF
Bickel
Susan
S
Bantia
Shanta
S
Keating
Michael J
MJ
Kantarjian
Hagop
H
Gandhi
Varsha
V
Ravandi
Farhad
F
D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011684:Purine Nucleosides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D012720:Severity of Illness Index; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011684:Purine Nucleosides; D011744:Pyrimidinones; C113101:forodesine; D011683:Purine-Nucleoside Phosphorylase; D010744:Phosphoric Monoester Hydrolases; D014740:Vidarabine; C024352:fludarabine