Drugs

, Volume 71, Issue 12, pp 1537–1550 | Cite as

Acute Myeloid Leukaemia

Optimal Management and Recent Developments
Therapy in Practice

Abstract

The current treatment of patients with acute myeloid leukaemia yields poor results, with expected cure rates in the order of 30–40% depending on the biological characteristics of the leukaemic clone. Therefore, new agents and schemas are intensively studied in order to improve patients’ outcomes. This review summarizes some of these new paradigms, including new questions such as which anthracycline is most effective and at what dose. High doses of daunorubicin have shown better responses in young patients and are well tolerated in elderly patients. Monoclonal antibodies are promising agents in good risk patients. Drugs blocking signalling pathways could be used in combination with chemotherapy or in maintenance with promising results. Epigenetic therapies, particularly after stem cell transplantation, are also discussed. New drugs such as clofarabine and flavopiridol are reviewed and the results of their use discussed. It is clear that many new approaches are under study and hopefully will be able to improve on the outcomes of the commonly used ‘7+3’ regimen of an anthracycline plus cytarabine with daunorubicin, which is clearly an ineffective therapy in the majority of patients.

Notes

Acknowledgements

This research was supported in part by the grant P01CA15396 from the National Cancer Institute. Dr Bolaños-Meade is an Investigator-2 and Dr Villela is an Investigator-1, Sistema Nacional de Investigadores (CONACYT, Mexico).

References

  1. 1.
    Löwenberg B, Downing JR, Burnett A. Acute myeloid leukemia. N Engl J Med 1999; 341(14): 1051–62PubMedGoogle Scholar
  2. 2.
    Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114(5): 937–51PubMedGoogle Scholar
  3. 3.
    Juliusson G, Antunovic P, Derolf A, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood 2009; 113(18): 4179–87PubMedGoogle Scholar
  4. 4.
    Surveillance Research Program, National Cancer Institute. Fast Stats: an interactive tool for access to SEER cancer statistics [online]. Available from URL: http://seer.cancer.gov/faststats [Accessed 2010 Dec 20]
  5. 5.
    Altekruse SF, Kosary CL, Krapcho M, et al. SEER cancer statistics review, 1975–2007. Bethesda (MD): National Cancer Institute, 2007Google Scholar
  6. 6.
    Villela L, Bolaños-Meade J. Blood and bone marrow transplantation for acute myeloid leukemia. Clin Leuk 2009; 2: E1 1–21Google Scholar
  7. 7.
    Swirsky DM, de Bastos M, Parish SE, et al. Features affecting outcome during remission induction of acute myeloid leukaemia in 619 adult patients. Br J Haematol 1986; 64: 435–53PubMedGoogle Scholar
  8. 8.
    Bolaños-Meade J, Guo C, Gojo I, et al. A phase II study of timed sequential therapy of acute myelogenous leukemia (AML) for patients over the age of 60: two cycle timed sequential therapy with topotecan, ara-C and mitoxantrone in adults with poor-risk AML. Leuk Res 2004; 28: 571–7PubMedGoogle Scholar
  9. 9.
    Castaigne S, Chevret S, Archimbaud E, et al. Randomized comparison of double induction and timed-sequential induction to a ‘3 + 7’ induction in adults with AML: long-term analysis of the Acute Leukemia French Association (ALFA) 9000 study. Blood 2004; 104: 2467–74PubMedGoogle Scholar
  10. 10.
    Bolaños-Meade J, Karp JE, Guo CF, et al. Timed sequential therapy of acute myelogenous leukemia in adults: a phase II study of retinoids in combination with the sequential administration of cytosine arabinoside, idarubicin and etoposide. Leuk Res 2003; 27: 313–21PubMedGoogle Scholar
  11. 11.
    Grimwade D, Walker H, Oliver F, et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood 1998; 92: 2322–33Google Scholar
  12. 12.
    Byrd JC, Mrozek K, Dodge RK, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002; 100: 4325–36PubMedGoogle Scholar
  13. 13.
    Marcucci G, Mrozek K, Ruppert AS, et al. Abnormal cytogenetics at date of morphologic complete remission predicts short overall and disease-free survival, and higher relapse rate in adult acute myeloid leukemia: results from cancer and leukemia group B study 8461. J Clin Oncol 2004; 22: 2410–8PubMedGoogle Scholar
  14. 14.
    Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001; 98: 1752–9PubMedGoogle Scholar
  15. 15.
    Schnittger S, Schoch C, Dugas M, et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 2002; 100: 59–66PubMedGoogle Scholar
  16. 16.
    Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002; 99: 4326–35PubMedGoogle Scholar
  17. 17.
    Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleo-phosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 2005; 352: 254–66PubMedGoogle Scholar
  18. 18.
    Boissel N, Renneville A, Biggio V, et al. Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood 2005; 106: 3618–20PubMedGoogle Scholar
  19. 19.
    Thiede C, Koch S, Creutzig E, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood 2006; 107: 4011–20PubMedGoogle Scholar
  20. 20.
    Gale RE, Green C, Allen C, et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM 1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 2008; 111:2776–84PubMedGoogle Scholar
  21. 21.
    Dohner 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: 453–74PubMedGoogle Scholar
  22. 22.
    Arber DA, Brunning RD, Le Beau MM, et al. Acute myeloid leukaemia with recurrent genetic abnormalities. In: Swerdlow SH, Campo E, Harris NL, et al. editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer (IARC), 2008: 110–23Google Scholar
  23. 23.
    Schnittger S, Schoch C, Kern W, et al. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 2005; 106: 3733–9PubMedGoogle Scholar
  24. 24.
    Falini B, Macijewski K, Weiss T, et al. Multilineage dysplasia has no impact on biologic, clinicopathologic, and prognostic features of AML with mutated nucleophosmin (NPM1). Blood 2010; 115: 3776–85PubMedGoogle Scholar
  25. 25.
    Díaz-Beyá M, Rozman M, Pratcorona M, et al. The prognostic value of multilineage dysplasia in de novo acute myeloid leukemia patients with intermediate-risk cytogenetics is dependent on NPM1 mutational status. Blood 2010; 116:6147–8PubMedGoogle Scholar
  26. 26.
    Falini B, Martelli MP, Bolli N, et al. Acute myeloid leukemia with mutated nucleophosmin (NPM1): is it a distinct entity? Blood 2011; 117(4): 1109–20PubMedGoogle Scholar
  27. 27.
    Zhang P, Iwasaki-Arai J, Iwasaki H, et al. Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha. Immunity 2004; 21: 853–63PubMedGoogle Scholar
  28. 28.
    Rosenbauer F, Tenen DG. Transcription factors in myeloid development: balancing differentiation with transformation. Nat Rev Immunol 2007; 7: 105–17PubMedGoogle Scholar
  29. 29.
    Fröhling S, Schlenk RF, Stolze I, et al. CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol 2004 15; 22: 624–33PubMedGoogle Scholar
  30. 30.
    Taskesen E, Bullinger L, Corbacioglu A. Prognostic impact, concurrent genetic mutations and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood 2011; 117(8): 2469–75PubMedGoogle Scholar
  31. 31.
    Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 1996; 10: 1911–8PubMedGoogle Scholar
  32. 32.
    Small D. FLT3 mutations: biology and treatment. Hematology Am Soc Hematol Educ Program 2006; 178–84Google Scholar
  33. 33.
    Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer 2003; 3: 650–65PubMedGoogle Scholar
  34. 34.
    Rai KR, Holland JF, Glidewell OJ, et al. Treatment of acute myelocytic leukemia: a study by cancer and leukemia group B. Blood 1981; 58: 1203–12PubMedGoogle Scholar
  35. 35.
    Dillman RO, Davis RB, Green MR, et al. A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B. Blood 1991; 78: 2520–6PubMedGoogle Scholar
  36. 36.
    Wahlin A, Hörnsten P, Hedenus M, et al. Mitoxantrone and cytarabine versus daunorubicin and cytarabine in previously untreated patients with acute myeloid leukemia. Cancer Chemother Pharmacol 1991; 28: 480–3PubMedGoogle Scholar
  37. 37.
    Archimbaud E, Jehn U, Thomas X, et al. Multicenter randomized phase II trial of idarubicin vs mitoxantrone, combined with VP-16 and cytarabine for induction/consolidation therapy, followed by a feasibility study of autologous peripheral blood stem cell transplantation in elderly patients with acute myeloid leukemia. Leukemia 1999; 13: 843–9PubMedGoogle Scholar
  38. 38.
    Löwenberg B, Suciu S, Archimbaud E, et al. Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy: the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon Group. J Clin Oncol 1998 Mar; 16: 872–81Google Scholar
  39. 39.
    Flasshove M, Meusers P, Schütte J, et al. Long-term survival after induction therapy with idarubicin and cytosine arabinoside for de novo acute myeloid leukemia. Ann Hematol 2000; 79: 533–42PubMedGoogle Scholar
  40. 40.
    Büchner T, Hiddemann W, Wörmann B, et al. Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group. Blood 1999; 93: 4116–24PubMedGoogle Scholar
  41. 41.
    The AML cooperative group. A systematic collaborative overview of randomized trials comparing idarubicin with daunorubicin (or other anthracyclines) as induction therapy for acute myeloid leukaemia. AML Collaborative Group. Br J Haematol 1998; 103: 100–9Google Scholar
  42. 42.
    Kimby E, Nygren P, Glimelius B. SBU-group. Swedish Council of Technology Assessment in Health Care. A systematic overview of chemotherapy effects in acute myeloid leukaemia. Acta Oncol 2001; 40: 231–52Google Scholar
  43. 43.
    Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 2009; 361: 1249–59PubMedGoogle Scholar
  44. 44.
    Löwenberg B, Ossenkoppele GJ, van Putten W, et al. Highdose daunorubicin in older patients with acute myeloid leukemia [published erratum appears in N Engl J Med 2010; 362 (12): 1155]. N Engl J Med 2009; 361: 1235–48PubMedGoogle Scholar
  45. 45.
    Mandelli F, Vignetti M, Suciu S, et al. Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10 [published erratum appears in J Clin Oncol 2010; 28: 1438]. J Clin Oncol 2009; 27: 5397–403PubMedGoogle Scholar
  46. 46.
    Masquelier M, Vitols S. Drastic effect of cell density on the cytotoxicity of daunorubicin and cytosine arabinoside. Biochem Pharmacol 2004; 67: 1639–46PubMedGoogle Scholar
  47. 47.
    Bogason A, Quartino AL, Lafolie P, et al. Inverse relationship between leukemic cell burden and plasma levels of daunorubicin in patients with acute myeloid leukemia. Br J Clin Pharmacol 2011; 71(4): 514–21PubMedGoogle Scholar
  48. 48.
    Gupta V, Tallman M, Weisdorf DJ. Allogeneic hematopoietic cell transplantation for adults with acute myeloid leukemia: myths, controversies, and unknowns. Blood 2011; 117(8): 2307–18PubMedGoogle Scholar
  49. 49.
    Becker H, Marcucci G, Maharry K, et al. Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: a Cancer and Leukemia Group B study. J Clin Oncol 2010; 28: 596–604PubMedGoogle Scholar
  50. 50.
    Büchner T, Hiddemann W, Berdel WE, et al. 6-Thioguanine, cytarabine, and daunorubicin (TAD) and high-dose cytarabine and mitoxantrone (HAM) for induction, TAD for consolidation, and either prolonged maintenance by reduced monthly TAD or TAD-HAM-TAD and one course of intensive consolidation by sequential HAM in adult patients at all ages with de novo acute myeloid leukemia (AML): a randomized trial of the German AML Cooperative Group. J Clin Oncol 2003; 21: 4496–504PubMedGoogle Scholar
  51. 51.
    Szotkowski T, Muzik J, Voglova J, et al. Prognostic factors and treatment outcome in 1,516 adult patients with de novo and secondary acute myeloid leukemia in 1999–2009 in 5 hematology intensive care centers in the Czech Republic. Neoplasma 2010; 57: 578–89PubMedGoogle Scholar
  52. 52.
    Abou-Jawde RM, Sobecks R, Pohlman B, et al. The role of post-remission chemotherapy for older patients with acute myelogenous leukemia. Leuk Lymphoma 2006; 47: 689–95PubMedGoogle Scholar
  53. 53.
    Kantarjian H, Ravandi F, O’Brien S, et al. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood 2010 Nov 25; 116: 4422–9PubMedGoogle Scholar
  54. 54.
    Pigneux A, Harousseau JL, Witz F, et al. Addition of lomustine to idarubicin and cytarabine improves the outcome of elderly patients with de novo acute myeloid leukemia: a report from the GOELAMS. J Clin Oncol 2010 Jun 20; 28: 3028–34PubMedGoogle Scholar
  55. 55.
    Kanemura N, Tsurumi H, Kasahara S, et al. Continuous drip infusion of low dose cytarabine and etoposide with granulocyte colony-stimulating factor for elderly patients with acute myeloid leukaemia ineligible for intensive chemotherapy. Hematol Oncol 2008 Mar; 26: 33–8PubMedGoogle Scholar
  56. 56.
    Yamauchi T, Negoro E, Arai H, et al. Combined low-dose cytarabine, melphalan and mitoxantrone for older patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. Anticancer Res 2007 Jul-Aug; 27: 2635–9PubMedGoogle Scholar
  57. 57.
    Whitman SP, Maharry K, Radmacher MD, et al. FLT3 internal tandem duplication associates with adverse outcome and gene- and microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Blood 2010; 116: 3622–6PubMedGoogle Scholar
  58. 58.
    Breccia M, Frustaci AM, Cannella L, et al. Comorbidities and FLT3-ITD abnormalities as independent prognostic indicators of survival in elderly acute myeloid leukaemia patients. Hematol Oncol 2009; 27: 148–53PubMedGoogle Scholar
  59. 59.
    Roboz GJ, Knovich MA, Bayer RL, et al. Efficacy and safety of gemtuzumab ozogamicin in patients with poor-prognosis acute myeloid leukemia. Leuk Lymphoma 2002; 43: 1951–5PubMedGoogle Scholar
  60. 60.
    Leopold LH, Berger MS, Cheng SC, et al. Comparative efficacy and safety of gemtuzumab ozogamicin mono-therapy and high-dose cytarabine combination therapy in patients with acute myeloid leukemia in first relapse. Clin Adv Hematol Oncol 2003; 1: 220–5PubMedGoogle Scholar
  61. 61.
    Cortes J, Tsimberidou AM, Alvarez R, et al. Mylotarg combined with topotecan and cytarabine in patients with refractory acute myelogenous leukemia. Cancer Che-mother Pharmacol 2002; 50: 497–500Google Scholar
  62. 62.
    Apostolidou E, Cortes J, Tsimberidou A, et al. Pilot study of gemtuzumab ozogamicin, liposomal daunorubicin, cytarabine and cyclosporine regimen in patients with refractory acute myelogenous leukemia. Leuk Res 2003; 27: 887–91PubMedGoogle Scholar
  63. 63.
    Chevallier P, Roland V, Mahé B, et al. Administration of mylotarg 4 days after beginning of a chemotherapy including intermediate-dose aracytin and mitoxantrone (MIDAM regimen) produces a high rate of complete hematologic remission in patients with CD33+ primary resistant or relapsed acute myeloid leukemia. Leuk Res 2005; 29: 1003–7PubMedGoogle Scholar
  64. 64.
    Martin MG, Augustin KM, Uy GL, et al. Salvage therapy for acute myeloid leukemia with fludarabine, cytarabine, and idarubicin with or without gemtuzumab ozogamicin and with concurrent or sequential G-CSF. Am J Hematol 2009; 84: 733–7PubMedGoogle Scholar
  65. 65.
    Larson RA, Sievers EL, Stadtmauer EA. Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer 2005; 104: 1442–52PubMedGoogle Scholar
  66. 66.
    McKoy JM, Angelotta C, Bennett CL, et al. Gemtuzumab ozogamicin-associated sinusoidal obstructive syndrome (SOS): an overview from the Research on Adverse Drug Events and Reports (RADAR) project. Leuk Res 2007; 31: 599–604PubMedGoogle Scholar
  67. 67.
    Amadori S, Suciu S, Selleslag D, et al. Randomized trial of two schedules of low-dose gemtuzumab ozogamicin as induction monotherapy for newly diagnosed acute myeloid leukaemia in older patients not considered candidates for intensive chemotherapy: a phase II study of the EORTC and GIMEMA leukaemia groups (AML-19). Br J Haematol 2010; 149(3): 376–82PubMedGoogle Scholar
  68. 68.
    McHayleh W, Foon K, Redner R, et al. Gemtuzumab ozogamicin as first-line treatment in patients aged 70 years or older with acute myeloid leukemia. Cancer 2010; 116: 3001–5PubMedGoogle Scholar
  69. 69.
    Candoni A, Martinelli G, Toffoletti E, et al. Gemtuzumab-ozogamicin in combination with fludarabine, cytarabine, idarubicin (FLAI-GO) as induction therapy in CD33-positive AML patients younger than 65 years. Leuk Res 2008; 32: 1800–8PubMedGoogle Scholar
  70. 70.
    Amadori S, Suciu S, Willemze R, et al. Sequential administration of gemtuzumab ozogamicin and conventional chemotherapy as first line therapy in elderly patients with acute myeloid leukemia: a phase II study(AML-15) of the EORTC and GIMEMA leukemia groups. Haematologica 2004; 89: 950–6PubMedGoogle Scholar
  71. 71.
    Eom KS, Kim HJ, Min WS, et al. Gemtuzumab ozogamicin in combination with attenuated doses of standard induction chemotherapy can successfully induce complete remission without increasing toxicity in patients with acute myeloid leukemia aged 55 or older. Eur J Haematol 2007; 79: 398–404PubMedGoogle Scholar
  72. 72.
    Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol 2011; 29(4): 369–77PubMedGoogle Scholar
  73. 73.
    US FDA. Mylotarg (gemtuzumab ozogamicin): market withdrawal [online]. Available from URL: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm216458.htm [Accessed 2011 Jul 21]
  74. 74.
    Scheinberg DA, Tanimoto M, McKenzie S, et al. Monoclonal antibody M195: a diagnostic marker for acute myelogenous leukemia. Leukemia 1989; 3: 440–5PubMedGoogle Scholar
  75. 75.
    Meloni G, Foa R, Vignett M, et al. Interleukin 2 may induce prolonged remissions in advanced acute myelogenous leukemia. Blood 1994; 84: 2158–63PubMedGoogle Scholar
  76. 76.
    Feldman EJ, Brandwein J, Stone R, et al. Phase III randomized multicenter study of a humanized anti-CD33 monoclonal antibody, lintuzumab, in combination with chemotherapy, versus chemotherapy alone in patients with refractory or first-relapsed acute myeloid leukemia. J Clin Oncol 2005; 23: 4110–6PubMedGoogle Scholar
  77. 77.
    Chapuis N, Park S, Leotoing L, et al. IkB kinase overcomes PI3K/Akt and ERK/MAPK to control FOXO3a activity in acute myeloid leukemia. Blood 2010; 116: 4240–50PubMedGoogle Scholar
  78. 78.
    Zebisch A, Czernilofsky AP, Keri G, et al. Signaling through RAS-RAF-MEK-ERK: from basics to bedside. Curr Med Chem 2007; 14: 601–23PubMedGoogle Scholar
  79. 79.
    Lübbert M, Oster W, Knopf HP, et al. N-RAS gene activation in acute myeloid leukemia: association with expression of interleukin-6. Leukemia 1993; 7: 1948–54PubMedGoogle Scholar
  80. 80.
    Récher C, Beyne-Rauzy O, Demur C, et al. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood 2005; 105: 2527–34PubMedGoogle Scholar
  81. 81.
    Lee J, Hwang J, Kim HS, et al. A comparison of gene expression profiles between primary human AML cells and AML cell line. Genes Genet Syst 2008; 83: 339–45PubMedGoogle Scholar
  82. 82.
    Karp JE, Lancet JE, Kaufmann SH, et al. Clinical and biologic activity of the farnesyltransferase inhibitor R1 15777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood 2001; 97: 3361–9PubMedGoogle Scholar
  83. 83.
    Harousseau JL, Lancet JE, Reiffers J, et al. A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib in patients with refractory or relapsed acute myeloid leukemia. Blood 2007; 109: 5151–6PubMedGoogle Scholar
  84. 84.
    Lancet JE, Gojo I, Gotlib J, et al. A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood 2007; 109: 1387–94PubMedGoogle Scholar
  85. 85.
    Harousseau JL, Martinelli G, Jedrzejczak WW, et al. A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older. Blood 2009; 114: 1166–73PubMedGoogle Scholar
  86. 86.
    Karp JE, Flatten K, Feldman EJ, et al. Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R1 15777, Zarnestra) combined with etoposide. Blood 2009; 113: 4841–52PubMedGoogle Scholar
  87. 87.
    Karp JE, Smith BD, Gojo I, et al. Phase II trial of tipifarnib as maintenance therapy in first complete remission in adults with acute myelogenous leukemia and poor-risk features. Clin Cancer Res 2008; 14: 3077–82PubMedGoogle Scholar
  88. 88.
    Crump M, Hedley D, Kamel-Reid S, et al. A randomized phase I clinical and biologic study of two schedules of sorafenib in patients with myelodysplastic syndrome or acute myeloid leukemia: a NCIC (National Cancer Institute of Canada) Clinical Trials Group Study. Leuk Lymphoma 2010; 51: 252–60PubMedGoogle Scholar
  89. 89.
    Metzelder S, Wang Y, Wollmer E, et al. Compassionate use of sorafenib in Flt3-ITD positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood 2009; 113: 6567–71PubMedGoogle Scholar
  90. 90.
    Ravandi F, Cortes JE, Jones D, et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol 2010; 28: 1856–62PubMedGoogle Scholar
  91. 91.
    Fischer T, Stone RM, Deangelo DJ. Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT 3. J Clin Oncol 2010; 28: 4339–45PubMedGoogle Scholar
  92. 92.
    Knapper S, Burnett AK, Littlewood T, et al. A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood 2006; 108: 3262–70PubMedGoogle Scholar
  93. 93.
    End DW, Smets G, Todd AV, et al. Characterization of the antitumor effects of the selective farnesyl protein trans-ferase inhibitor R115777 in vivo and in vitro. Cancer Res 2001; 61: 131–7PubMedGoogle Scholar
  94. 94.
    Hotte SJ, Hirte HW. BAY 43-9006: early clinical data in patients with advanced solid malignancies. Curr Pharm Des 2002; 8: 2249–53PubMedGoogle Scholar
  95. 95.
    Zhang W, Konopleva M, Ruvolo VR, et al. Sorafenib induces apoptosis of AML cells via Bim-mediated activation of the intrinsic apoptotic pathway. Leukemia 2008; 22: 808–18PubMedGoogle Scholar
  96. 96.
    Knapper S, Mills KI, Gilkes AF, et al. The effects of lestaurtinib (CEP701) and PKC412 on primary AML blasts: the induction of cytotoxicity varies with dependence on FLT3 signaling in both FLT3-mutated and wild-type cases. Blood 2006; 108: 3494–503PubMedGoogle Scholar
  97. 97.
    Cancer and Leukemia Group B. Daunorubicin, cytarabine, and midostaurin in treating patients with newly diagnosed acute myeloid leukemia [ClinicalTrials.gov identifier NCT00651261]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrial.gov [Accessed 2011 Apr 7]
  98. 98.
    Yang J, Ikezoe T, Nishioka C, et al. Inhibition of mTORC1 by RAD001 (everolimus) potentiates the effects of 1,25-dihydroxyvitamin D(3) to induce growth arrest and differentiation of AML cells in vitro and in vivo. Exp Hematol 2010; 38: 666–76PubMedGoogle Scholar
  99. 99.
    Janus A, Linke A, Cebula B, et al. Rapamycin, the mTOR kinase inhibitor, sensitizes acute myeloid leukemia cells, HL-60 cells, to the cytotoxic effect of arabinozide cytarabine. Anticancer Drugs 2009; 20: 693–701PubMedGoogle Scholar
  100. 100.
    Figueroa ME, Lugthart S, Li Y, et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 2010; 17: 13–27PubMedGoogle Scholar
  101. 101.
    Bullinger L, Ehrich M, Döhner K, et al. Quantitative DNA methylation predicts survival in adult acute myeloid leukemia. Blood 2010; 115: 636–42PubMedGoogle Scholar
  102. 102.
    Götze K, Platzbecker U, Giagounidis A, et al. Azacitidine for treatment of patients with myelodysplastic syndromes (MDS): practical recommendations of the German MDS Study Group. Ann Hematol 2010; 89: 841–50PubMedGoogle Scholar
  103. 103.
    Silverman LR, McKenzie DR, Peterson BL, et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol 2006; 24: 3895–903PubMedGoogle Scholar
  104. 104.
    Buckstein R, Yee K, Wells RA. The Canadian Consortium on Evidence-based Care in MDS. 5-Azacytidine in myelodysplastic syndromes: a clinical practice guideline. Cancer Treat Rev 2011; 37(2): 160–7Google Scholar
  105. 105.
    Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009; 10: 223–32PubMedGoogle Scholar
  106. 106.
    Hollenbach PW, Nguyen AN, Brady H, et al. A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One 2010; 5(2): e9001PubMedGoogle Scholar
  107. 107.
    Bolaños-Meade J, Smith BD, Gore SD, et al. 5-Azacytidine as salvage treatment in relapsed myeloid tumors after allogeneic bone marrow transplantation. Biol Blood Marrow Transplant 2011; 17(5): 754–8PubMedGoogle Scholar
  108. 108.
    Czibere A, Bruns I, Kröger N, et al. 5-Azacytidine for the treatment of patients with acute myeloid leukemia or myelodysplastic syndrome who relapse after allo-SCT: a retrospective analysis. Bone Marrow Transplant 2010; 45: 872–6PubMedGoogle Scholar
  109. 109.
    Villela L, Anders V, Bolaños-Meade J. Predonor lymphocyte infusion treatment with 5-azacytidine as salvage treatment in relapsed acute myeloid leukaemia secondary to myelodysplastic syndrome. Anticancer Drugs 2010; 21:469PubMedGoogle Scholar
  110. 110.
    Candelaria M, Herrera A, Labardini J, et al. Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome: preliminary results of a phase-II trial. Ann Hematol 2011; 90: 379–87PubMedGoogle Scholar
  111. 111.
    Decker RH, Dai Y, Grant S. The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in human leukemia cells (U937) through the mitochondrial rather than the receptor-mediated pathway. Cell Death Differ 2001; 8: 715–24PubMedGoogle Scholar
  112. 112.
    Karp JE, Smith BD, Levis MJ, et al. Sequential flavopiridol, cytosine arabinoside, and mitoxantrone: a phase II trial in adults with poor-risk acute myelogenous leukemia. Clin Cancer Res 2007; 13: 4467–73PubMedGoogle Scholar
  113. 113.
    Karp JE, Blackford A, Smith BD. Clinical activity of sequential flavopiridol, cytosine arabinoside, and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia. Leuk Res 2010; 34: 877–82PubMedGoogle Scholar
  114. 114.
    Karp JE, Smith BD, Resar LS, et al. Phase I and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias. Blood 2011; 117(12): 3302–10PubMedGoogle Scholar
  115. 115.
    Bonate PL, Arthaud L, Cantrell Jr WR, et al. Discovery and development of clofarabine: a nucleoside analogue for treating cancer. Nat Rev Drug Discov 2006; 5: 855–63PubMedGoogle Scholar
  116. 116.
    Burnett AK, Russell NH, Kell J, et al. European development of clofarabine as treatment for older patients with acute myeloid leukemia considered unsuitable for intensive chemotherapy. J Clin Oncol 2010; 28: 2389–95PubMedGoogle Scholar
  117. 117.
    Kantarjian HM, Erba HP, Claxton D, et al. Phase II study of clofarabine monotherapy in previously untreated older adults with acute myeloid leukemia and unfavorable prognostic factors. J Clin Oncol 2010; 28: 549–55PubMedGoogle Scholar
  118. 118.
    Ribeiro RC, Rego E. Management of APL in developing countries: epidemiology, challenges and opportunities for international collaboration. Hematology Am Soc Hematol Educ Program 2006: 162–8Google Scholar
  119. 119.
    Buitrón-Santiago N, Arteaga-Ortiz L, Rosas-López A, et al. Acute myeloid leukemia in adults: experience at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán from 2003 to 2008. Rev Invest Clin 2010; 62: 100–8PubMedGoogle Scholar
  120. 120.
    Ruiz-Argüelles GJ, Apreza-Molina MG, Alemán-Hoey DD, et al. Outpatient supportive therapy after induction to remission therapy in adult acute myelogenous leukaemia (AML) is feasible: a multicentre study. Eur J Haematol 1995; 54: 18–20PubMedGoogle Scholar
  121. 121.
    Pavlovsky S, Gonzalez Llaven J, Garcia Martinez MA, et al. A randomized study of mitoxantrone plus cytarabine versus daunomycin plus cytarabine in the treatment of previously untreated adult patients with acute non-lymphocytic leukemia. Ann Hematol 1994; 69: 11–5PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  1. 1.Centro de Innovación y Transferencia en Salud, Servicio de Hematología del Centro Médico Zambrano HellionEscuela de Medicina del Instituto Tecnológico y de Estudios Superiores de MonterreyMonterreyMexico
  2. 2.“George W. Santos” Bone Marrow Transplant Service, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkinsthe Johns Hopkins University School of MedicineBaltimoreUSA

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