Disease relevance of Clofarabine

• Clofarabine (2-chloro-2'-fluoro-deoxy-9-beta-D-arabinofuranosyladenine) is a second-generation nucleoside analog with activity in acute leukemias [1].
• In a phase 2 study, 62 patients with relapsed and refractory acute myeloid leukemia (AML; n = 31), myelodysplastic syndrome (MDS; n = 8), chronic myeloid leukemia in blastic phase (CMLBP; n = 11), and acute lymphocytic leukemia (ALL; n = 12) received 40 mg/m2 clofarabine intravenously over 1 hour daily for 5 days, every 3 to 6 weeks [2].
• Clofarabine and cytarabine combination as induction therapy for acute myeloid leukemia (AML) in patients 50 years of age or older [3].
• Purpose: To define the maximum-tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of clofarabine, given as a 1-hour infusion daily for 5 days, in patients with solid tumors and with acute leukemia [4].
• Clinical and pharmacokinetic study of clofarabine in chronic lymphocytic leukemia: strategy for treatment [5].

High impact information on Clofarabine

• Clofarabine was given at 40 mg/m2 as a 1-hour intravenous infusion for 5 days (days 2 to 6) followed 4 hours later by cytarabine at 1 g/m2/d as a 2-hour intravenous infusion for 5 days (days 1 to 5) [3].
• Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias [1].
• In summary, clofarabine is active in acute leukemias and MDS; cellular pharmacokinetics may have prognostic significance [2].
• At 40 mg/m(2), the median plasma clofarabine level was 1.5 micro mol/L (range, 0.42 to 3.2 micro mol/L; n = 7) [4].
• CONCLUSION: Levels of clofarabine triphosphate at higher doses and prolonged maintenance of clofarabine triphosphate in leukemic lymphocytes provide a rationale to treat CLL in a weekly clofarabine schedule [5].

Chemical compound and disease context of Clofarabine

• Given the clinical activity of clofarabine in adult acute leukemias, it is of interest to conduct a detailed characterization of the cellular pharmacology of clofarabine triphosphate and its relationship to clinical responses [6].
• PURPOSE: Based on its mechanistic similarity to fludarabine and cladribine and the success of these analogues for treatment of chronic lymphocytic leukemia (CLL), we hypothesized that clofarabine would be effective for indolent leukemias [5].
• Dose-limiting toxicities were nonhematologic: hepatotoxicity for clofarabine and neurotoxicity for nelarabine [7].
• PURPOSE: To evaluate the efficacy and safety of clofarabine, a novel deoxyadenosine analog, in pediatric patients with refractory or relapsed acute lymphoblastic leukemia (ALL) [8].

Biological context of Clofarabine

• Clofarabine also disrupts the integrity of mitochondrial membranes, resulting in programmed cell death [9].
• Like other adenosine nucleosides, clofarabine acts by inhibiting ribonucleotide reductase and DNA polymerase, thereby depleting the amount of intracellular deoxynucleoside triphosphates available for DNA replication and also resulting in premature DNA chain termination [10].

Anatomical context of Clofarabine

• We studied the pharmacokinetics and cerebrospinal fluid penetration of clofarabine in a nonhuman primate model [11].
• Cellular pharmacokinetic studies showed a median clofarabine triphosphate concentration in CLL lymphocytes of 1.5 micromol/L (range, 0.2-2.3 micromol/L; n = 9) [5].
• Evaluation of the contribution of clofarabine to central nervous system preventive therapy should be considered in future studies [11].
• Mechanisms of acquired resistance to three purine analogues, 2-chloro-2'-deoxyadenosine (cladribine, CdA), 9-beta-D-arabinofuranosyl-2-fluoroadenine (fludarabine, Fara-A), and 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine (clofarabine, CAFdA) were investigated in a human T-lymphoblastic leukemia cell line (CCRF-CEM) [12].
• Clofarabine was the major analyte found in myocardium (>97% region of integration) and liver (>94% region of integration) [13].

Associations of Clofarabine with other chemical compounds

• Recently four novel PNA: clofarabine (CAFdA), nelarabine, immucillin H (BCX-1777, forodesine) and 8-chloroadenosine (8-Cl-Ado) have been synthesized and introduced into clinical trials [14].
• In vitro cytotoxicity of nelarabine, clofarabine and flavopiridol in paediatric acute lymphoblastic leukaemia [15].
• Promising therapeutic results have been reported for the antiCD33 monoclonal antibody conjugated with calicheamicin and the new nucleoside analog clofarabine; preliminary studies indicate that FLT3, farnesyl-transferase and bcl-2 inhibitors are active in relapsed AML [16].

Gene context of Clofarabine

• The interactions between 2-Cl and its surrounding hydrophobic residues contribute to the high catalytic efficiency of dCK for clofarabine [17].
• This loss is reduced or absent in clofarabine-treated FLT3 mutant cells [18].

Analytical, diagnostic and therapeutic context of Clofarabine

• The present study was conducted to determine the efficacy and cellular pharmacology during clinical trials of single-agent clofarabine in CLL [5].
• Plasma and cerebrospinal fluid (CSF) samples were obtained at specified intervals and the clofarabine concentration determined by reverse-phase high-pressure liquid chromatography with mass spectroscopy [11].
• PATIENTS AND METHODS: In a phase II, open-label, multicenter study, 61 pediatric patients with refractory or relapsed ALL received clofarabine 52 mg/m2 intravenously over 2 hours daily for 5 days, every 2 to 6 weeks [8].
• Remissions were durable enough to allow patients to proceed to hematopoietic stem-cell transplantation (HSCT) after clofarabine [8].

References