nelarabine and Leukemia--T-Cell

T-cell haematological malignancies are uncommon, difficult to treat and, with the exception of T-cell acute lymphoblastic leukaemia, often associated with a poor prognosis. Nelarabine (2-amino-9-beta-D-arabinosyl-6-methoxy-9H-guanine), a synthesised guanosine nucleoside and water-soluble prodrug of ara-G (9-beta-D-arabinofuranosylguanine), has recently been approved by the FDA for the treatment of relapsed/refractory T-cell acute lymphoblastic leukaemia and T-cell lymphoblastic lymphoma in adults and children. Similar to other nucleoside analogues, nelarabine acts by inhibiting DNA synthesis and inducing apoptosis in susceptible cells. Ara-G itself is a water-insoluble molecule, making its clinical use difficult. However, nelarabine is water soluble and rapidly converted to ara-G in vivo. Interestingly, it has been demonstrated that ara-GTP accumulates more readily in T-cells than in B-cells, and this discovery created interest in the development of nelarabine for the treatment of T-cell malignancies. The results of early-phase clinical trials evaluating the use of nelarabine in adults and children with refractory T-cell malignancies have been promising. This article describes the development, pharmacology, toxicity and clinical activity of nelarabine, as well as discusses its potential role in the treatment of T-cell haematological malignancies.

Topics: Animals; Arabinonucleosides; Clinical Trials as Topic; Humans; Leukemia, T-Cell; Treatment Outcome

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

Nelarabine (compound 506U78), a water soluble prodrug of 9-b-d-arabinofuranosylguanine, is converted to ara-GTP in T lymphoblasts. We sought to define the response rate of nelarabine in children and young adults with refractory or recurrent T-cell disease.. We performed a phase II study with patients stratified as follows: stratum 1: > or = 25% bone marrow blasts in first relapse; stratum 2: > or = 25% bone marrow blasts in > or = second relapse; stratum 3: positive CSF; stratum 4: extramedullary (non-CNS) relapse. The initial nelarabine dose was 1.2 g/m2 daily for 5 consecutive days every 3 weeks. There were two dose de-escalations due to neurotoxicity on this or other studies. The final dose was 650 mg/m2/d for strata 1 and two patients and 400 mg/m2/d for strata 3 and four patients.. We enrolled 121 patients (106 assessable for response) at the final dose levels. Complete plus partial response rates at the final dose levels were: 55% in stratum 1; 27% in stratum 2; 33% in stratum 3; and 14% in stratum 4. There were 31 episodes of > or = grade 3 neurologic adverse events in 27 patients (18% of patients).. Nelarabine is active as a single agent in recurrent T-cell leukemia, with a response rate more than 50% in first bone marrow relapse. The most significant adverse events associated with nelarabine administration are neurologic. Further studies are planned to determine whether the addition of nelarabine to front-line therapy for T-cell leukemia in children will improve survival.

Topics: Adolescent; Adult; Arabinonucleosides; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Infant; Infusions, Intravenous; Leukemia, T-Cell; Male; Maximum Tolerated Dose; Neoplasm Staging; Recurrence; Risk Assessment; Survival Rate; Treatment Outcome

In vitro investigations with arabinosylguanine (ara-G) demonstrated potent cytotoxicity 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.. During a 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.. 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 [t1/2]=17 minutes) was faster than the elimination of ara-G (t1/2=3.7 hours). Median peak concentrations of ara-GTP were 23, 42, 85, and 93 micromol/L at 20, 30, 40, and 60 mg/kg, respectively. T-lymphoblasts accumulated significantly (P=.0008) higher peak arabinsylguanosine triphosphate (ara-GTP) (median, 140 micromol/L; n=7) compared with other diagnoses (median, 50 micromol/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 micromol/L) compared with patients who failed to respond (median, 44 micromol/L).. 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.

Topics: Adult; Antineoplastic Agents; Arabinonucleosides; Arabinonucleotides; Child; Child, Preschool; Dose-Response Relationship, Drug; Guanosine Triphosphate; Hematologic Neoplasms; Humans; Leukemia, B-Cell; Leukemia, T-Cell; Multicenter Studies as Topic; Prodrugs; Time Factors; Treatment Outcome

Topics: Adult; Arabinonucleosides; Child; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Leukemia, T-Cell