nelarabine and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

To present the pharmacology and pharmacokinetics of nelarabine, 9-beta-D-arabinofuranosylguanine (ara-G) and intraleukemic cellular pharmacokinetics of 9-beta-D-arabinofuranosylguanine triphosphate (ara-GTP) generated from the administration of nelarabine, and clinical and safety information relative to nelarabine use in the treatment of hematologic malignancies.. MEDLINE (1966-December 2004) was searched using the English-language key terms 2-amino-6-methoxypurine arabinoside, 506U78, and nelarabine. Data were also obtained from published abstracts.. Clinical studies evaluating the pharmacokinetics of nelarabine, ara-G, and cellular ara-GTP and use of nelarabine, alone or in combination with other agents for the treatment of hematologic malignancies, were included in this review.. Nelarabine is the water-soluble, 6-methoxy analog of 9-beta-D-ara-G. Nelarabine is readily converted to ara-G by endogenous adenosine deaminase. The half-life of nelarabine is approximately 15 minutes compared with 2-4 hours for ara-G. The clearance of ara-G is higher in children than in adults (0.312 vs 0.213 L x h(-1) x kg(-1)). Intracellular ara-GTP elimination is slow relative to nelarabine and ara-G. In pediatric and adult patients, neurologic toxicity is dose limiting. Severe myelosuppression was not consistently observed. Major responses were seen in patients with T-cell malignancies. Patients who responded had significantly higher intracellular ara-GTP concentrations compared with those who did not respond.. Nelarabine is an effective ara-G prodrug. Nelarabine has significant activity against malignant T-cells and appears to be an important addition to treatments of various leukemias.

Topics: Arabinonucleosides; Area Under Curve; Clinical Trials as Topic; Fatigue; Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, T-Cell; Meta-Analysis as Topic

T-cell lymphoid blastic phase (BP) transformation is rare in chronic myelogenous leukemia (CML). 2-amino-9-beta-D-arabinosyl-6-methoxy-9H-guanine (GW506U78), a prodrug of arabinosylguanine (ara-G), is effective in T-cell leukemias.. The authors present a case of a 48-year-old male with Philadelphia chromosome (Ph) positive CML and T-cell lymphoid BP after 17 months in the chronic phase.. Plasma pharmacokinetic studies after an infusion of GW506U78 at a dose of 40 mg/kg showed GW506U78 concentrations of 60 microM, and a peak ara-G concentration of 260 microM in the plasma. Cellular ara-G triphosphate (ara-GTP) concentration in the peripheral blood T-lymphoblasts was 80 microM at the end of GW506U78 infusion and reached a maximum of 150 microM. The patient achieved a complete response that lasted 13 months. Severe neurotoxicity related to GW506U78 was observed.. GW506U78 showed antileukemic activity against Ph positive T-cell BP CML. Neurotoxicity was dose-limiting in this patient. Treatment with GW506U78 and modulation of ara-GTP concentrations are therapeutic strategies that require further exploration in T-cell malignancies. Investigation of other dosing schedules may limit neurotoxicity.

Topics: Antineoplastic Agents; Arabinonucleosides; Arabinonucleotides; Blast Crisis; Guanosine Triphosphate; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Remission Induction; T-Lymphocytes

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.. 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.. 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).. 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.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Arabinonucleotides; Biomarkers; Female; Guanosine Triphosphate; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Prolymphocytic; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Treatment Outcome; Vidarabine