Compound GW506U78 in refractory hematologic malignancies: Relationship between cellular pharmacokinetics and clinical response

Purpose: In vitro investigations with arabinosylguanine (ara-G) demonstrated potent cytatoxicity to T-lymphoblastoid cell lines. The goals of the present study were to evaluate GW506U78, a prodrug of ara-G, against human hematologic malignancies and to determine its pharmacokinetics in plasma and cells. Patients and Methods: During o phase I multicenter trial of GW506U78, 26 patients were treated at M.D. Anderson Cancer Center (MDACC). Daily doses between 20 and 60 mg/kg were administered for 5 days. Parallel plasma and cellular pharmacokinetic studies were conducted. Results: Complete (n = 5) or partial remission (n = 5) was achieved in T-cell acute lymphoblastic leukemia (T-ALL), T-lymphoid blast crisis, T-lymphoma, and B- cell chronic lymphocytic leukemia (B-CLL) (n = 13). In contrast, patients with B-ALL, B-lymphoma, acute myelogenous leukemia (AMI), or T-CLL did not respond. Peak plasma concentrations of GW506U78 and ara-G were dose- dependent. The elimination of GW506U78 (half life [t 1/4 ] = 17 minutes) was faster than the elimination of ara-G (t 1/4 = 3.7 hours). Median peak concentrations of ara-GTP were 23, 42, 85, and 93 μmol/L at 20, 30, 40, and 60 mg/kg, respectively. T-lymphoblasts accumulated significantly (P = .0008) higher peak arabinsyl-guanosine triphosphate (ara-GTP) (median, 140 μmol/L; n = 7) compared with other diagnoses (median, 50 μmol/L; n = 9) and normal mononuclear cells (n = 3). The ara-GTP elimination was slow in all diagnoses (median, > 24 hours). Responders accumulated significantly (P = .0005) higher levels of ara-GTP (median, 157 μmol/L) compared with patients who failed to respond (median, 44 μmol/L). Conclusion: GW506U78 is an effective prodrug and a potent agent for hematologic malignancies with major efficacy in T- cell diseases. The pharmacokinetics of ara-GTP in leukemia cells are strongly correlated with clinical responses to GW506U78.