submit to the journals

Elacytarabine – A New Agent in the Treatment of Relapsed/Refractory Acute Myeloid Leukaemia

European Oncology & Haematology, 2012;8(2):111–15 DOI: http://doi.org/10.17925/EOH.2012.08.02.111

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.

Acknowledgement: Editorial assistance was provided by Janet Manson at Touch Briefings and funded by Clavis Pharma.
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.
Received: April 12, 2012 Accepted: April 19, 2012
Correspondence: Norbert Vey, Department of Haematology, Institut Paoli-Calmettes, 232 Boulevard Sainte Marguerite, 13009 Marseille, France. E: veyn@marseille.fnclcc.fr
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 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/m2) and high (2–3 g/m2) doses is the mainstay of second-line treatment for relapsed AML.5 Common salvage regimens are cytarabine for six days (2–3 g/m2 every 12 hours) or a combination of cytarabine (3 g/m2 every 12 hours on days 1, 3, 5 and 7) with either daunorubicin (50 mg/m2) or idarubicin (10 mg/m2) 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
References:
  1. Estey E, Döhner H, Acute myeloid leukaemia, Lancet, 2006;368:1894–1907.
  2. Fey M, Dreyling M, Acute myeloblastic leukemia in adult patients: ESMO clinical recommendations for diagnosis, treatment and follow-up, Ann Oncol, 2009;20(Suppl. 4):100–1.
  3. Thomas X, Dombret H, Timed-sequential chemotherapy as induction and/or consolidation regimen for younger adults with acute myelogenous leukemia, Hematology, 2007;12:15–28.
  4. Tsurumi H, Kanemura N, Hara T, et al., Therapeutic strategy of untreated de novo acute myeloid leukemia in the elderly: the efficacy of continuous drip infusion with low dose cytarabine and etoposide, J Cancer Res Clin Oncol, 2007;133:547–53.
  5. Döhner H, Estey EH, Amadori S, et al., Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet, Blood, 2010;115:453–74.
  6. Hann IM, Webb DK, Gibson BE, Harrison CJ, MRC trials in childhood acute myeloid leukaemia, Ann Hematol, 2004;83(Suppl. 1):S108–12.
  7. Burnett A, Wetzler M, Lowenberg B, Therapeutic advances in acute myeloid leukemia, J Clin Oncol, 2011;29:487–94.
  8. Kufe DW, Major PP, Egan EM, Beardsley GP, Correlation of cytotoxicity with incorporation of ara-C into DNA, J Biol Chem, 1980;255:8997–8900.
  9. Major PP, Egan EM, Beardsley GP, et al., Lethality of human myeloblasts correlates with the incorporation of arabinofuranosylcytosine into DNA, Proc Natl Acad Sci U S A, 1981;78:3235–9.
  10. Grant S, Ara-C: cellular and molecular pharmacology, Adv Cancer Res, 1998;72:197–233.
  11. White JC, Rathmell JP, Capizzi RL, Membrane transport influences the rate of accumulation of cytosine arabinoside in human leukemia cells, J Clin Invest, 1987;79:380–7.
  12. Baker WJ, Royer GL Jr, Weiss RB, Cytarabine and neurologic toxicity, J Clin Oncol, 1991;9:679–93.
  13. Lamba JK, Genetic factors influencing cytarabine therapy, Pharmacogenomics, 2009;10:1657–74.
  14. Cai J, Damaraju VL, Groulx N, et al., Two distinct molecular mechanisms underlying cytarabine resistance in human leukemic cells, Cancer Res, 2008;68:2349–57.
  15. Cros E, Jordheim L, Dumontet C, Galmarini CM, Problems related to resistance to cytarabine in acute myeloid leukemia, Leuk Lymphoma, 2004;45:1123–32.
  16. Zhang J, Visser F, King KM, et al., The role of nucleoside transporters in cancer chemotherapy with nucleoside drugs, Cancer Metastasis Rev, 2007;26:85–110.
  17. Fernandez-Calotti P, Jordheim LP, Giordano M, et al., Substrate cycles and drug resistance to 1-beta-D-arabinofuranosylcytosine (araC), Leuk Lymphoma, 2005;46:335–46.
  18. Mitra AK, Crews KR, Pounds S, et al., Genetic variants in cytosolic 5’-nucleotidase II are associated with its expression and cytarabine sensitivity in HapMap cell lines and in patients with acute myeloid leukemia, J Pharmacol Exp Ther, 2011;339:9–23.
  19. Boleti H, Coe IR, Baldwin SA, et al., Molecular identification of the equilibrative NBMPR-sensitive (es) nucleoside transporter and demonstration of an equilibrative NBMPR-insensitive (ei) transport activity in human erythroleukemia (K562) cells, Neuropharmacology, 1997;36:1167–79.
  20. Clarke ML, Mackey JR, Baldwin SA, et al., The role of membrane transporters in cellular resistance to anticancer nucleoside drugs, Cancer Treat Res, 2002;112:27–47.
  21. Estey E, Plunkett W, Dixon D, et al., Variables predicting response to high dose cytosine arabinoside therapy in patients with refractory acute leukemia, Leukemia, 1987;1:580–3.
  22. Galmarini CM, Thomas X, Calvo F, et al., Potential mechanisms of resistance to cytarabine in AML patients, Leuk Res, 2002;26:621–9.
  23. Hubeek I, Stam RW, Peters GJ, et al., The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia, Br J Cancer, 2005;93:1388–94.
  24. Takagaki K, Katsuma S, Kaminishi Y, et al., Gene-expression profiling reveals down-regulation of equilibrative nucleoside transporter 1 (ENT1) in Ara-C-resistant CCRF-CEM-derived cells, J Biochem, 2004;136:733–40.
  25. Galmarini CM, Thomas X, Calvo F, et al., In vivo mechanisms of resistance to cytarabine in acute myeloid leukaemia, Br J Haematol, 2002;117:860–8.
  26. Wiley JS, Taupin J, Jamieson GP, et al., Cytosine arabinoside transport and metabolism in acute leukemias and T cell lymphoblastic lymphoma, J Clin Invest, 1985;75:632–42.
  27. Gati WP, Paterson AR, Larratt LM, et al., Sensitivity of acute leukemia cells to cytarabine is a correlate of cellular es nucleoside transporter site content measured by flow cytometry with SAENTA-fluorescein, Blood, 1997;90:346–53.
  28. Wiley JS, Jones SP, Sawyer WH, Paterson AR, Cytosine arabinoside influx and nucleoside transport sites in acute leukemia, J Clin Invest, 1982;69:479–89.
  29. Adema AD, Smid K, Losekoot N, et al., Metabolism and accumulation of the lipophilic deoxynucleoside analogs elacytarabine and CP-4126, Invest New Drugs, 15 October 2011 [Epub ahead of print].
  30. Galmarini CM, Myhren F, Sandvold ML, CP-4055 and CP-4126 are active in ara-C and gemcitabine-resistant lymphoma cell lines, Br J Haematol, 2009;144:273–5.
  31. Breistøl K, Balzarini J, Sandvold ML, et al., Antitumor activity of P-4055 (elaidic acid-cytarabine) compared to cytarabine in metastatic and s.c. human tumor xenograft models, Cancer Res, 1999;59:2944–9.
  32. Bergman AM, Kuiper CM, Voorn DA, et al., Antiproliferative activity and mechanism of action of fatty acid derivatives of arabinofuranosylcytosine in leukemia and solid tumor cell lines, Biochem Pharmacol, 2004;67:503–11.
  33. O’Brien S, Rizzieri D, Vey N, et al., A Phase I/II Study with CP-4055 in Patients with Hematologic Malignancies, Presented at: American Society of Hematology Annual Meeting, San Francisco, US, 6–9 December 2008; Abstract 949.
  34. Giles FJ, Vey N, Rizzieri D, et al., Phase I and pharmacokinetic study of elacytarabine, a novel 5’-elaidic acid derivative of cytarabine, in adults with refractory hematological malignancies, Leukemia, 6 January 2012 [Epub ahead of print].
  35. O’Brien S, Rizzieri D, Padmanabhan S, et al., A Phase I Study with CP-4055 and Idarubicin in Patients with Refractory/Relapsed AML, Presented at: 14th Congress of the European Hematology Association, Berlin, 4–7 June 2009;Abstract 1485.
  36. Giles F, Rizzieri D, Ravandi F, et al., Elacytarabine, a novel 5’-elaidic acid derivative of cytarabine, and idarubicin combination is active in refractory acute myeloid leukemia, Leuk Res, 2012;36:e71–3.
  37. O’Brien S, Rizzieri D, Vey N, et al., Elacytarabine has single-agent activity in patients with advanced acute myeloid leukaemia, Br J Haematol, 2012 [In press].
  38. Giles F, O’Brien S, Cortes J, et al., Outcome of patients with acute myelogenous leukemia after second salvage therapy, Cancer, 2005;104:547–54.
  39. Rizzieri D, Vey N, Gobbi M, et al., CLAVELA, a Randomised Phase III Study of Elacytarabine (CP-4055) vs. Investigator’s Choice in Patients with Late Stage Acute Myeloid leukemia (AML), Presented at: American Society of Clinical Oncology Annual Meeting, Chicago, US, 3–7 June 2011; Abstract 83258.
  40. Figueroa ME, Lugthart S, Li Y, et al., DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia, Cancer Cell, 2010;17:13–27.
  41. Rizzieri D, Krug U, Schlenk RF, et al., A Phase II Study of Elacytarabine (CP-4055) plus Idarubicin as Second Course Remission-Induction Therapy in Patients with Acute Myeloid Leukaemia, Presented at: American Society of Clinical Oncology Annual Meeting, Chicago, US, 3–7 June 2011; Abstract 83277.
  42. Rizzieri D, Vey N, Schlenk RF, et al., A Phase II Study of Elacytarabine/Idarubicin as Second-course Remission-induction Therapy in Patients with AML (CP4055-205), Presented at: American Society of Hematology Annual Meeting, San Diego, US, 8–13 December 2011; Abstract 42825.
Keywords: Acute myeloid leukaemia (AML), elacytarabine, ara-CTP, cytarabine, cellular uptake, human equilibrative nucleoside transporter-1 (hENT1)