HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Evaluation of the combination of nelarabine and fludarabine in leukemias: clinical response, pharmacokinetics, and pharmacodynamics in leukemia cells.

AbstractPURPOSE:
A pilot protocol was designed to evaluate the efficacy of fludarabine with nelarabine (the prodrug of arabinosylguanine [ara-G]) in patients with hematologic malignancies. The cellular pharmacokinetics was investigated to seek a relationship between response and accumulation of ara-G triphosphate (ara-GTP) in circulating leukemia cells and to evaluate biochemical modulation of cellular ara-GTP metabolism by fludarabine triphosphate.
PATIENTS AND METHODS:
Nine of the 13 total patients had indolent leukemias, including six whose disease failed prior fludarabine therapy. Two patients had T-acute lymphoblastic leukemia, one had chronic myelogenous leukemia, and one had mycosis fungoides. Nelarabine (1.2 g/m(2)) was infused on days 1, 3, and 5. On days 3 and 5, fludarabine (30 mg/m(2)) was administered 4 hours before the nelarabine infusion. Plasma and cellular pharmacokinetic measurements were conducted during the first 5 days.
RESULTS:
Seven patients had a partial or complete response, six of whom had indolent leukemias. The disease in four responders had failed prior fludarabine therapy. The median peak intracellular concentrations of ara-GTP were significantly different (P =.001) in responders (890 micromol/L, n = 6) and nonresponders (30 micromol/L, n = 6). Also, there was a direct relationship between the peak fludarabine triphosphate and ara-GTP in each patient (r = 0.85). The cellular elimination of ara-GTP was slow (median, 35 hours; range, 18 to > 48 hours). The ratio of ara-GTP to its normal counterpart, deoxyguanosine triphosphate, was higher in each patient (median, 42; range, 14 to 1,092) than that of fludarabine triphosphate to its normal counterpart, deoxyadenosine triphosphate (median, 2.2; range, 0.2 to 27).
CONCLUSION:
Fludarabine plus nelarabine is an effective, well-tolerated regimen against leukemias. Clinical responses suggest the need for further exploration of nelarabine against fludarabine-refractory diseases. Determination of ara-GTP levels in the target tumor population may provide a prognostic test for the activity of nelarabine.
AuthorsV Gandhi, W Plunkett, S Weller, M Du, M Ayres, C O Rodriguez Jr, P Ramakrishna, G L Rosner, J P Hodge, S O'Brien, M J Keating
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 19 Issue 8 Pg. 2142-52 (Apr 15 2001) ISSN: 0732-183X [Print] United States
PMID11304766 (Publication Type: Clinical Trial, Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Arabinonucleosides
  • Arabinonucleotides
  • Biomarkers
  • nelarabine
  • 9-beta-D-arabinofuranosylguanosine 5'-triphosphate
  • Guanosine Triphosphate
  • Vidarabine
  • fludarabine
Topics
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Arabinonucleosides (administration & dosage, pharmacokinetics, pharmacology)
  • Arabinonucleotides (analysis, metabolism)
  • Biomarkers (analysis)
  • Female
  • Guanosine Triphosphate (analogs & derivatives, analysis, metabolism)
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy)
  • Leukemia, Prolymphocytic (drug therapy)
  • Male
  • Middle Aged
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy)
  • Prognosis
  • Treatment Outcome
  • Vidarabine (administration & dosage, analogs & derivatives, pharmacokinetics, pharmacology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: