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Haematological Malignancies Elacytarabine – A New Agent in the Treatment of Relapsed/Refractory Acute Myeloid Leukaemia Norbert Vey Professor, Head of Leukaemia Service, Department of Haematology, Paoli-Calmettes Institute, Marseille, France Abstract The prognosis for patients with relapsed acute myeloid leukaemia (AML) is poor, and effective treatments for this patient group remain a substantially unmet clinical need. Elacytarabine is a promising new cytotoxic nucleoside agent made by an esterification reaction between cytarabine and elaidic acid, currently in development for use in the treatment of relapsed/refractory AML. Unlike cytarabine, cellular uptake of elacytarabine is independent of human equilibrative nucleoside transporter-1 (hENT-1) and results in prolonged intracellular retention of the active nucleoside. In addition, elacytarabine inhibits DNA synthesis for twice the duration seen with cytarabine and exhibits a different intracellular distribution. A Phase I trial in patients with AML identified a recommended dose of 2,000 mg/m²/day for five days and showed limited non-haematological side effects, liver toxicity being dose-limiting. Elacytarabine can be safely combined with idarubicin. A recent Phase II trial demonstrated an improved complete remission rate and overall survival with elacytarabine as a single agent in patients with advanced AML, as compared with a historical control group treated with second salvage therapy. Following these encouraging results, the results of an ongoing Phase III clinical trial comparing elacytarabine with the investigator’s choice of standard of care are awaited with interest. Keywords Acute myeloid leukaemia (AML), elacytarabine, ara-CTP, cytarabine, cellular uptake, human equilibrative nucleoside transporter-1 (hENT1) Disclosure: Norbert Vey has received honoraria from Celgene, BMS and Innate Pharma. Acknowledgement: Editorial assistance was provided by Janet Manson at Touch Briefings and funded by Clavis Pharma. Received: 12 April 2012 Accepted: 19 April 2012 Citation: European Oncology & Haematology, 2012;8(2):111–15 Correspondence: Norbert Vey, Department of Haematology, Institut Paoli-Calmettes, 232 Boulevard Sainte Marguerite, 13009 Marseille, France. E: Support: The publication of this article was funded by Clavis Pharma. The views and opinions expressed are those of the author and not necessarily those of Clavis Pharma. Acute myeloid leukaemia (AML) is a genetically heterogeneous group of leukaemias that result from clonal transformation of haematopoietic precursors through the acquisition of chromosomal rearrangements and multiple gene mutations. In the absence of treatment, AML progresses rapidly, resulting in bone marrow failure, anaemia, fatal infection, bleeding and organ infiltration. The incidence of AML increases with age, with 70 years the median age at diagnosis. 1 In Europe, the incidence of AML in adults is 5–8 cases/100,000/year, while the mortality rate is 4–6 cases/100,000/year. 2 Treatment of AML consists of two phases: induction therapy, which aims to produce complete remission (CR), and post-remission (consolidation) therapy, which aims to prolong the CR. For the past 30 years, the standard induction therapy for AML has consisted of cytarabine in conjunction with an anthracycline, such as daunorubicin or idarubicin. 1 In general, following induction therapy, the CR rate is 50–75 % in adult patients. 1,3,4 The major determinants of prognosis for patients with AML are age, cytogenetics and FLT3/NPM1 gene mutation profile. 5 After CR, however, the majority of patients relapse, giving rise to a more resistant leukaemia. 6 The prognosis for relapsed or refractory AML patients is poor and there is no standard treatment. 7 For patients who achieve CR, AML may be curable by stem cell transplantation. The introduction of new drugs and therapeutic regimens that have been shown to achieve CR in a greater number of patients could potentially © TOUCH BRIEFINGS 2012 result in more transplants being performed, and consequently increased cure rates in relapsed or refractory AML patients. New therapies for the treatment of relapsed/refractory AML represent an unmet clinical need. This article will discuss the use of elacytarabine, a promising new agent in the treatment of relapsed/refractory AML. Current Treatment Options for Refractory/Relapsed Acute Myeloid Leukaemia At the current time, there is no treatment specifically approved for relapsed/refractory AML. Cytarabine (1-ß-D-arabinofuranosylcytosine, ara-C) given at intermediate (1 g/m 2 ) and high (2–3 g/m 2 ) doses is the mainstay of second-line treatment for relapsed AML. 5 Common salvage regimens are cytarabine for six days (2–3 g/m 2 every 12 hours) or a combination of cytarabine (3 g/m 2 every 12 hours on days 1, 3, 5 and 7) with either daunorubicin (50 mg/m 2 ) or idarubicin (10 mg/m 2 ) on days 2, 4 and 6. 5 Cytarabine is a deoxynucleoside analogue which, following intracellular conversion to the active triphosphate metabolite of cytarabine (ara-CTP) causes irreversible inhibition of DNA synthesis by becoming permanently bound into elongating DNA strands. 8,9 This in turn leads to chain termination, inhibition of further DNA synthesis, DNA fragmentation and induction of apoptosis. 10 111