title: Phase I trial of nelarabine in indolent leukemias.
abstract: OBJECTIVE
  To test whether nelarabine is an effective agent for indolent leukemias and to evaluate whether there is a relationship between cellular pharmacokinetics of the analog triphosphate and clinical responses.
  
  
  METHODS
  Thirty-five patients with relapsed/refractory leukemias (n = 24, B-cell chronic lymphocytic leukemia and n = 11, T-cell prolymphocytic leukemia) were entered onto three different protocols. For schedule A, patient received nelarabine daily for 5 days, whereas for schedule B, nelarabine was administered on days 1, 3, and 5. Schedule C was similar to schedule B except that fludarabine was also infused. Plasma and cellular pharmacokinetics were studied during the first cycle.
  
  
  RESULTS
  Responses were achieved in 20%, 15%, and 63% of patients receiving schedule A, B, and C, respectively. Histologic category, number of prior therapies, and fludarabine refractoriness did not influence the response rate. The most common nonhematologic toxicity was peripheral neuropathy. Grade 4 neutropenia and thrombocytopenia complicated 23% and 26% of courses respectively, and were significantly more frequent among patients with pre-existing marrow failure. Pharmacokinetics of plasma nelarabine and arabinosylguanine (ara-G) and of cellular ara-G triphosphate (ara-GTP) were similar in the two groups of diagnoses, and the elimination of ara-GTP from leukemia cells was slow (median, > 24 hours). The median peak intracellular concentrations of ara-GTP were significantly different (P = .0003) between responders (440 micromol/L; range, 35 to 1,438 micromol/L; n = 10) and nonresponders (50 micromol/L; range, 22 to 178 micromol/L; n = 15).
  
  
  CONCLUSIONS
  Nelarabine is an effective regimen against indolent leukemias, and combining it with fludarabine was most promising. Determination of tumor cell ara-GTP levels may provide a predictive test for response to nelarabine.
authors.affiliation: Department of Experimental Therapeutics, Box 71, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. vgandhi@mdanderson.org
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
authors.forename: Constantine
authors.initials: C
authors.lastname: Tam
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Roxanne C
authors.initials: RC
authors.lastname: Jewell
authors.forename: Carlos O
authors.initials: CO
authors.lastname: Rodriguez
authors.forename: Susan
authors.initials: S
authors.lastname: Lerner
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D001087:Arabinonucleosides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001088:Arabinonucleotides / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D004359:Drug Therapy, Combination; D005260:Female; D006160:Guanosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy*; D015461:Leukemia, Prolymphocytic, T-Cell / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D001088:Arabinonucleotides; C104457:nelarabine; C022206:9-beta-D-arabinofuranosylguanosine 5'-triphosphate; D006160:Guanosine Triphosphate; D004248:DNA (Cytosine-5-)-Methyltransferases; D014740:Vidarabine; C024352:fludarabine