5--oleoyl-cytarabine and Leukemia--Myeloid--Acute

Cytosine arabinoside (cytarabine or Ara-C) has been one of the cornerstones of treatment of acute myeloid leukemia since its approval in 1969. Standard induction therapy worldwide for all patients deemed fit for treatment (excluding those with acute promyelocytic leukemia) remains unchanged for over 40 years and consists of Ara-C administered by continuous infusion in combination with a topoisomerase II inhibitor (e.g., daunorubicin, idarubicin and mitoxantrone). Despite decades of clinical investigation, the optimum dose of both agents still remains unclear. Although higher doses of Ara-C have been shown to improve response rates, the elderly poorly tolerate these regimens. Resistance mechanisms also develop or may be present at diagnosis resulting in poor outcomes. Elacytarabine (CP-4055), an elaidic acid ester of Ara-C, has been developed using lipid vector technology in an attempt to overcome these limitations. Clinical data are encouraging, with evidence suggesting that this novel agent is circumventing resistance mechanisms but retaining the potent antileukemic efficacy of Ara-C.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Drug Delivery Systems; Drug Discovery; Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy

For the last twenty years, significant progress in Molecular and Cellular Biology has resulted in a better characterization and understanding of the biology and prognosis of acute myeloid leukemia (AML). These achievements have provided new opportunities for the development of innovative, more effective therapies. Novel agents potentially useful in the treatment of patients with AML include new formulations of established drugs, newer nucleoside analogs, molecular target drugs, monoclonal antibodies and other agents. Three newer nucleoside analogs, clofarabine, troxacitabine and sapacitabine have been recently investigated in patients with AML. Two methylation inhibitors, 5-azacyticline and decitabine are pyrimidine nucleoside analogs of cytidine which can be incorporated into RNA and/or DNA. Lower doses of these agents are active in AML and have been extensively investigated, especially in secondary AML and AML in elderly patients. Tipifarnib and lonafarnib are orally available farnesyltransferase inhibitors with in vitro and in vivo activity against AML. In recent years, FLT3 inhibitors, lestaurinib, tandutinib and PKC 412 have been developed and tested in AML. The preclinical observations and clinical studies indicate that FLT3 inhibitors are promising agents in the treatment of FLT3 mutated AML patients, especially when used in combinations with chemotherapy. Several newer MDR inhibitors, including valspodar (PSC-833) and zosuquidar trihydrochloride have been also tested for the treatment of relapsed AML. This article reviews the various classes of AML targets and drugs that are under early phase clinical evaluation, especially those that are likely to enter clinical practice in the near future.

Topics: Adenine Nucleotides; Animals; Arabinonucleosides; Azacitidine; Benzamides; Clofarabine; Cytarabine; Cytosine; Daunorubicin; Decitabine; Dioxolanes; Farnesyltranstransferase; Histone Deacetylase Inhibitors; Humans; Hydrazines; Imatinib Mesylate; Leukemia, Myeloid, Acute; Liposomes; Piperazines; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; TOR Serine-Threonine Kinases; Valproic Acid; Vascular Endothelial Growth Factor Receptor-1

Ara-C (cytarabine arabinoside) is a deoxycytidine analog that has an established role in the treatment of hematologic malignancies, especially acute myeloid leukemia. Resistance to ara-C occurs and impacts negatively on survival. To combat this, an elaidic acid ester of ara-C, called elacytarabine, has been developed. This novel agent is highly efficacious in cells with demonstrable resistance to the parent agent, including in solid tumor xenografts.. The mechanisms that account for the increased clinical activity of elacytarabine are discussed, including its ability to bypass the specialized transmembrane nucleoside transport system on which ara-C depends, its prolonged retention within the cell and its alternative effect on the cell cycle. The development and synthesis and pharmacokinetics are outlined, with emphasis on lipid vector technology. Ten clinical trials involving elacytarabine, either as monotherapy or part of a combination regimen, have been carried out in both solid tumor and hematologic malignancies. The efficacy and side effect profile results are summarized.. Clinical trials in patients with hematological malignancies are reporting very encouraging efficacy results with an acceptable side effect profile. Elacytarabine has the potential to play an important role in the treatment of multiple malignancies in the future and results from an ongoing Phase III clinical trial are eagerly awaited.

Topics: Antineoplastic Agents; Cytarabine; Drug Delivery Systems; Drug Discovery; Drug Resistance, Neoplasm; Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy

Unlike cytarabine, cellular entry of Elacytarabine, the elaidic acid ester derivative of cytarabine, is independent of the human equilibrative nucleoside transporter 1 (hENT1). This phase II study tested whether the hENT1 blast expression level can be used as a predictive marker for cytarabine response and if the efficacy of elacytarabine is independent of hENT1 expression. A total of 51 patients with acute myeloid leukemia (AML) induction failure were given elacytarabine-idarubicin as a second induction course. The hENT1 expression level was analyzed prior to first induction and/or prior to treatment with elacytarabine. The overall response rate (ORR) was 41% and the safety profile was manageable. There is a trend suggesting that hENT1 expression influences response to cytarabine, but not sufficient to support it as a biomarker for guiding treatment. Further, we conclude that the activity of elacytarabine is not significantly predicted by the hENT1 expression level.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cytarabine; Equilibrative Nucleoside Transporter 1; Female; Gene Expression; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Induction Chemotherapy; Leukemia, Myeloid, Acute; Male; Middle Aged; Treatment Outcome; Young Adult

Elacytarabine is the elaidic acid ester derivative of cytarabine, designed to enter cells independently of nucleoside transporters. Effects of elacytarabine on QT interval, serum lipid profile and clinical activity were investigated in 43 relapsed/refractory AML patients. Mean maximum increase in corrected QT interval of 24( ± 29)ms occurred 48 h after elacytarabine infusion without associated arrhythmias or clinical symptoms. A non-clinically significant, elacytarabine exposure-dependent increase in cholesterol was caused by a cholesterol rich lipoprotein depleted of apolipoprotein B formed by infused phospholipids complexing cholesterol. Elacytarabine is clinically active in relapsed/refractory AML: overall response rate (CR + CRi) was 44% (16/36 with 7 non-evaluable patients) and adverse events were manageable. Clinical Trials.gov Identifier: NCT01258816.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Cholesterol; Cytarabine; Drug Administration Schedule; Electrocardiography; Female; Heart; Humans; Leukemia, Myeloid, Acute; Lipoproteins; Male; Middle Aged; Recurrence; Treatment Outcome

Most patients with acute myeloid leukemia (AML) eventually experience relapse. Relapsed/refractory AML has a dismal prognosis and currently available treatment options are generally ineffective. The objective of this large, international, randomized clinical trial was to investigate the efficacy of elacytarabine, a novel elaidic acid ester of cytarabine, versus the investigator's choice of one of seven commonly used AML salvage regimens, including high-dose cytarabine, multiagent chemotherapy, hypomethylating agents, hydroxyurea, and supportive care.. A total of 381 patients with relapsed/refractory AML were treated in North America, Europe, and Australia. Investigators selected a control treatment for individual patients before random assignment. The primary end point was overall survival (OS).. There were no significant differences in OS (3.5 v 3.3 months), response rate (23% v 21%), or relapse-free survival (5.1 v 3.7 months) between the elacytarabine and control arms, respectively. There was no significant difference in OS among any of the investigator's choice regimens. Prolonged survival was only achieved in a few patients in both study arms whose disease responded and who underwent allogeneic stem-cell transplantation.. Neither elacytarabine nor any of the seven alternative treatment regimens provided clinically meaningful benefit to these patients. OS in both study arms and for all treatments was extremely poor. Novel agents, novel clinical trial designs, and novel strategies of drug development are all desperately needed for this patient population.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Cytogenetic Analysis; Disease-Free Survival; Female; Humans; Hyperbilirubinemia; Hypercholesterolemia; International Cooperation; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Middle Aged; Prognosis; Recurrence; Treatment Failure

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Cytarabine; Female; Half-Life; Humans; Idarubicin; Leukemia, Myeloid, Acute; Male; Maximum Tolerated Dose; Middle Aged; Young Adult

Elacytarabine is a novel cytotoxic nucleoside analogue, independent of nucleoside transporters (e.g. human Equilibrative Nucleoside Transporter 1 [hENT1]) for cell uptake, and mechanisms of action similar to those of cytarabine. This Phase II study assessed the efficacy and safety of elacytarabine in patients with advanced stage acute myeloid leukaemia (AML). Patients received 2000 mg/m(2) per d continuously i.v. during days 1-5 every 3 weeks. Patients were matched by six risk factors with historical controls; remission rate (assessed after 1 or 2 cycles) and 6-month survival were compared. Sixty-one patients, median age 58 years, were enrolled; 52% had five or six risk factors. The remission rate was 18% (95% confidence interval: 9-30%) vs. 4% in controls (P < 0·0001), 6-month survival rate was 43%, median overall survival was 5·3 months (vs. 1·5 months); 10 patients (16%) were referred for stem cell transplantation after treatment. Side effects were predictable and manageable. The most common grade 3/4 non-haematological adverse events were febrile neutropenia, hypokalemia, fatigue, hyponatraemia, dyspnoea and pyrexia. Thirty-day all-cause mortality, after start of treatment, was 13% vs. 25% in controls. Elacytarabine has monotherapy activity in patients with advanced AML. This study provides proof-of-concept that lipid esterification of nucleoside analogues is clinically relevant.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Cytarabine; Female; Humans; Infusions, Intravenous; Leukemia, Myeloid, Acute; Male; Middle Aged; Referral and Consultation; Remission Induction; Risk Factors; Stem Cell Transplantation; Survival Rate; Treatment Outcome

Elacytarabine (formerly CP-4055) is a lipid-conjugated derivative of the nucleoside analog cytarabine. Elacytarabine was rationally designed to circumvent cytarabine resistance related to decreased cellular uptake, due to the ability of the lipophilic drug moiety to enter the cell without the requirement of specialized nuclear transport proteins, including the hENT1. In preclinical and clinical studies, elacytarabine has demonstrated both safety and efficacy in acute myeloid leukemia (AML), with noteworthy activity among the cytarabine-refractory AML population. Elacytarabine was granted orphan drug designation status from the European Commission in 2007 and from the US FDA in 2008, with a fast-track approval designation from the FDA in 2010. Results of a recent randomized Phase III clinical trial, however, failed to show superiority of elacytarabine over the investigator's choice of therapy for relapsed or refractory AML.

Topics: Cytarabine; Drug Approval; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Humans; Leukemia, Myeloid, Acute; Randomized Controlled Trials as Topic; Treatment Outcome