Histone deacetylase inhibition in the treatment of acute myeloid leukemia: the effects of valproic acid on leukemic cells, and the clinical and experimental evidence for combining valproic acid with other antileukemic agents

Hanne Fredly, Bjørn Tore Gjertsen, Oystein Bruserud, Hanne Fredly, Bjørn Tore Gjertsen, Oystein Bruserud

Abstract

Several new therapeutic strategies are now considered for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy, including modulation of protein lysine acetylation through inhibition of histone deacetylases (HDACs). These enzymes alter the acetylation of several proteins, including histones and transcription factors, as well as several other proteins directly involved in the regulation of cell proliferation, differentiation and apoptosis. Valproic acid (VPA) is a HDAC inhibitor that has been investigated in several clinical AML studies, usually in combination with all-trans retinoic acid (ATRA) for treatment of patients unfit for intensive chemotherapy, for example older patients, and many of these patients have relapsed or primary resistant leukemia. The toxicity of VPA in these patients is low and complete hematological remission lasting for several months has been reported for a few patients (<5% of included patients), but increased peripheral blood platelet counts are seen for 30 to 40% of patients and may last for up to 1 to 2 years. We review the biological effects of VPA on human AML cells, the results from clinical studies of VPA in the treatment of AML and the evidence for combining VPA with new targeted therapy. However, it should be emphasized that VPA has not been investigated in randomized clinical studies. Despite this lack of randomized studies, we conclude that disease-stabilizing treatment including VPA should be considered especially in unfit patients, because the possibility of improving normal blood values has been documented in several studies and the risk of clinically relevant toxicity is minimal.

References

    1. Estey E, Döhner H. Acute myeloid leukaemia. Lancet. 2006;368:1894–1907. doi: 10.1016/S0140-6736(06)69780-8.
    1. Büchner T, Berdel WE, Haferlach C, Haferlach T, Schnittger S, Müller-Tidow C, Braess J, Spiekermann K, Kienast J, Staib P, Grüneisen A, Kern W, Reichle A, Maschmeyer G, Aul C, Lengfelder E, Sauerland MC, Heinecke A, Wörmann B, Hiddemann W. Age-related risk profile and chemotherapy dose response in acute myeloid leukemia: a study by the German Acute Myeloid Leukemia Cooperative Group. J Clin Oncol. 2009;27:61–69.
    1. Burnett A, Wetzler M, Löwenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011;29:487–494. doi: 10.1200/JCO.2010.30.1820.
    1. Cornelissen JJ, Gratwohl A, Schlenk RF, Sierra J, Bornhäuser M, Juliusson G, Råcil Z, Rowe JM, Russell N, Mohty M, Löwenberg B, Socié G, Niederwieser D, Ossenkoppele GJ. The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach Nat Rev. Clin Oncol. 2012;9:579–590.
    1. Appelbaum FR, Gundacker H, Head DR, Slovak ML, Willman CL, Godwin JE, Anderson JE, Petersdorf SH. Age and acute myeloid leukemia. Blood. 2006;107:3481–3485. doi: 10.1182/blood-2005-09-3724.
    1. Kantarjian H, Ravandi F, O'Brien S, Cortes J, Faderl S, Garcia-Manero G, Jabbour E, Wierda W, Kadia T, Pierce S, Shan J, Keating M, Freireich EJ. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood. 2010;116:4422–4429. doi: 10.1182/blood-2010-03-276485.
    1. Giles FJ, Borthakur G, Ravandi F, Faderl S, Verstovsek S, Thomas D, Wierda W, Ferrajoli A, Kornblau S, Pierce S, Albitar M, Cortes J, Kantarjian H. The haematopoietic cell transplantation comorbidity index score is predictive of early death and survival in patients over 60 years of age receiving induction therapy for acute myeloid leukaemia. Br J Haematol. 2007;136:624–627. doi: 10.1111/j.1365-2141.2006.06476.x.
    1. Juliusson G, Antunovic P, Derolf A, Lehmann S, Möllgård L, Stockelberg D, Tidefelt U, Wahlin A, Höglund M. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood. 2009;113:4179–4187. doi: 10.1182/blood-2008-07-172007.
    1. Walter RB, Othus M, Borthakur G, Ravandi F, Cortes JE, Pierce SA, Appelbaum FR, Kantarjian HA, Estey EH. Prediction of early death after induction therapy for newly diagnosed acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment assignment. J Clin Oncol. 2011;29:4417–4423. doi: 10.1200/JCO.2011.35.7525.
    1. Delcuve GP, Khan DH, Davie JR. Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors. Clin Epigenetics. 2012;4:5. doi: 10.1186/1868-7083-4-5.
    1. Kuendgen A, Gattermann N. Valproic acid for the treatment of myeloid malignancies. Cancer. 2007;110:943–954. doi: 10.1002/cncr.22891.
    1. Blaheta RA, Nau H, Michaelis M, Cinatl J Jr. Valproate and valproate-analogues: potent tools to fight against cancer. Curr Med Chem. 2002;9:1417–1433. doi: 10.2174/0929867023369763.
    1. Göttlicher M, Minucci S, Zhu P, Krämer OH, Schimpf A, Giavara S, Sleeman JP, Lo Coco F, Nervi C, Pelicci PG, Heinzel T. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001;20:6969–6978. doi: 10.1093/emboj/20.24.6969.
    1. Quintás-Cardama A, Santos FP, Garcia-Manero G. Histone deacetylase inhibitors for the treatment of myelodysplastic syndrome and acute myeloid leukemia. Leukemia. 2011;25:226–235. doi: 10.1038/leu.2010.276.
    1. Tickenbrock L, Klein HU, Trento C, Hascher A, Göllner S, Bäumer N, Kuss R, Agrawal S, Bug G, Serve H, Thiede C, Ehninger G, Stadt UZ, McClelland M, Wang Y, Becker A, Koschmieder S, Berdel WE, Dugas M, Müller-Tidow C. Study Alliance Leukemia Group. Increased HDAC1 deposition at hematopoietic promoters in AML and its association with patient survival. Leuk Res. 2011;35:620–625. doi: 10.1016/j.leukres.2010.11.006.
    1. Bradbury CA, Khanim FL, Hayden R, Bunce CM, White DA, Drayson MT, Craddock C, Turner BM. Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia. 2005;19:1751–1759. doi: 10.1038/sj.leu.2403910.
    1. Bug G, Schwarz K, Schoch C, Kampfmann M, Henschler R, Hoelzer D, Ottmann OG, Ruthardt M. Effect of histone deacetylase inhibitor valproic acid on progenitor cells of acute myeloid leukemia. Haematologica. 2007;92:542–545. doi: 10.3324/haematol.10758.
    1. Cheng YC, Lin H, Huang MJ, Chow JM, Lin S, Liu HE. Downregulation of c-Myc is critical for valproic acid-induced growth arrest and myeloid differentiation of acute myeloid leukemia. Leuk Res. 2007;31:1403–1411. doi: 10.1016/j.leukres.2007.03.012.
    1. Cimino G, Lo-Coco F, Fenu S, Travaglini L, Finolezzi E, Mancini M, Nanni M, Careddu A, Fazi F, Padula F, Fiorini R, Spiriti MA, Petti MC, Venditti A, Amadori S, Mandelli F, Pelicci PG, Nervi C. Sequential valproic acid/all-trans retinoic acid treatment reprograms differentiation in refractory and high-risk acute myeloid leukemia. Cancer Res. 2006;66:8903–8911. doi: 10.1158/0008-5472.CAN-05-2726.
    1. Corsetti MT, Salvi F, Perticone S, Baraldi A, De Paoli L, Gatto S, Pietrasanta D, Pini M, Primon V, Zallio F, Tonso A, Alvaro MG, Ciravegna G, Levis A. Hematologic improvement and response in elderly AML/RAEB patients treated with valproic acid and low-dose Ara-C. Leuk Res. 2011;35:991–997. doi: 10.1016/j.leukres.2011.02.021.
    1. Forthun RB, Sengupta T, Skjeldam HK, Lindvall JM, McCormack E, Gjertsen BT, Nilsen H. Cross-species functional genomic analysis identifies resistance genes of the histone deacetylase inhibitor valproic acid. PLoS One. 2012;7:e48992. doi: 10.1371/journal.pone.0048992.
    1. Fredly H, Reikvam H, Gjertsen BT, Bruserud O. Disease-stabilizing treatment with all-trans retinoic acid and valproic acid in acute myeloid leukemia: Serum hsp70 and hsp90 levels and serum cytokine profiles are determined by the disease, patient age, and anti-leukemic treatment. Am J Hematol. 2012;87:368–376. doi: 10.1002/ajh.23116.
    1. Fredly H, Stapnes Bjørnsen C, Gjertsen BT, Bruserud Ø. Combination of the histone deacetylase inhibitor valproic acid with oral hydroxyurea or 6-mercaptopurin can be safe and effective in patients with advanced acute myeloid leukaemia--a report of five case. Hematology. 2010;15:338–343. doi: 10.1179/102453310X12647083620967.
    1. Goodyear O, Agathanggelou A, Novitzky-Basso I, Siddique S, McSkeane T, Ryan G, Vyas P, Cavenagh J, Stankovic T, Moss P, Craddock C. Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia. Blood. 2010;116:1908–1918. doi: 10.1182/blood-2009-11-249474.
    1. Gul H, Marquez-Curtis LA, Jahroudi N, Larratt LM, Janowska-Wieczorek A. Valproic acid exerts differential effects on CXCR4 expression in leukemic cells. Leuk Res. 2010;34:235–242. doi: 10.1016/j.leukres.2009.05.014.
    1. Hauswald S, Duque-Afonso J, Wagner MM, Schertl FM, Lubbert M, Peschel C, Keller U, Licht T. Histone deacetylase inhibitors induce a very broad, pleiotropic anticancer drug resistance phenotype in acute myeloid leukemia cells by modulation of multiple ABC transporter genes. Clin Cancer Res. 2009;15:3705–3715. doi: 10.1158/1078-0432.CCR-08-2048.
    1. Iacomino G, Medici MC, Russo GL. Valproic acid sensitizes K562 erythroleukemia cells to TRAIL/Apo2L-induced apoptosis. Anticancer Res. 2008;28:855–864.
    1. Khanim FL, Bradbury CA, Arrazi J, Hayden RE, Rye A, Basu S, MacWhannell A, Sawers A, Griffiths M, Cook M, Freeman S, Nightingale KP, Grimwade D, Falciani F, Turner BM, Bunce CM, Craddock C. Elevated FOSB-expression; a potential marker of valproate sensitivity in AML. Br J Haematol. 2009;144:332–341. doi: 10.1111/j.1365-2141.2008.07449.x.
    1. Langenkamp U, Siegler U, Jörger S, Diermayr S, Gratwohl A, Kalberer CP, Wodnar-Filipowicz A. Human acute myeloid leukemia CD34 + CD38- stem cells are susceptible to allorecognition and lysis by single KIR-expressing natural killer cells. Haematologica. 2009;94:1590–1594. doi: 10.3324/haematol.2009.005967.
    1. Leiva M, Moretti S, Soilihi H, Pallavicini I, Peres L, Mercurio C, Dal Zuffo R, Minucci S, de Thé H. Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL. Leukemia. 2012;26:1630–1637. doi: 10.1038/leu.2012.39.
    1. Liu S, Klisovic RB, Vukosavljevic T, Yu J, Paschka P, Huynh L, Pang J, Neviani P, Liu Z, Blum W, Chan KK, Perrotti D, Marcucci G. Targeting AML1/ETO-histone deacetylase repressor complex: a novel mechanism for valproic acid-mediated gene expression and cellular differentiation in AML1/ETO-positive acute myeloid leukemia cells. J Pharmacol Exp Ther. 2007;321:953–960. doi: 10.1124/jpet.106.118406.
    1. Lu X, Ohata K, Kondo Y, Espinoza JL, Qi Z, Nakao S. Hydroxyurea upregulates NKG2D ligand expression in myeloid leukemia cells synergistically with valproic acid and potentially enhances susceptibility of leukemic cells to natural killer cell-mediated cytolysis. Cancer Sci. 2010;101:609–615. doi: 10.1111/j.1349-7006.2009.01439.x.
    1. Patra SK, Deb M, Patra A. Molecular marks for epigenetic identification of developmental and cancer stem cells. Clin Epigenetics. 2011;2:27–53. doi: 10.1007/s13148-010-0016-0.
    1. Poggi A, Catellani S, Garuti A, Pierri I, Gobbi M, Zocchi MR. Effective in vivo induction of NKG2D ligands in acute myeloid leukaemias by all-trans-retinoic acid or sodium valproate. Leukemia. 2009;23:641–648. doi: 10.1038/leu.2008.354.
    1. Skavland J, Jørgensen KM, Hadziavdic K, Hovland R, Jonassen I, Bruserud Ø, Gjertsen BT. Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia. Blood Cancer J. 2011;1:e4. doi: 10.1038/bcj.2011.2.
    1. Smetana K, Zápotocký M. The effect of a histone deacetylase inhibitor - valproic acid - on nucleoli in human leukaemic myeloblasts. Folia Biol (Praha) 2010;56:201–205.
    1. Stapnes C, Ryningen A, Hatfield K, Øyan AM, Eide GE, Corbascio M, Kalland KH, Gjertsen BT, Bruserud Ø. Functional characteristics and gene expression profiles of primary acute myeloid leukaemia cells identify patient subgroups that differ in susceptibility to histone deacetylase inhibitors. Int J Oncol. 2007;31:1529–1538.
    1. St-Germain JR, Chen J, Li Q. Involvement of PML nuclear bodies in CBP degradation through the ubiquitin-proteasome pathway. Epigenetics. 2008;3:342–349. doi: 10.4161/epi.3.6.7203.
    1. Kuendgen A, Knipp S, Fox F, Strupp C, Hildebrandt B, Steidl C, Germing U, Haas R, Gattermann N. Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. Ann Hematol. 2005;84(Suppl 1):61–66.
    1. Kuendgen A, Schmid M, Schlenk R, Knipp S, Hildebrandt B, Steidl C, Germing U, Haas R, Dohner H, Gattermann N. The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia. Cancer. 2006;106:112–119. doi: 10.1002/cncr.21552.
    1. Breitman TR, Collins SJ, Keene BR. Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid. Blood. 1981;57:1000–1004.
    1. Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008;111:2505–2515. doi: 10.1182/blood-2007-07-102798.
    1. Park JH, Tallman MS. Treatment of acute promyelocytic leukemia without cytotoxic chemotherapy. Oncology. 2011;25:733–741.
    1. Mrózek K, Bloomfield CD. Clinical significance of the most common chromosome translocations in adult acute myeloid leukemia. J Natl Cancer Inst Monogr. 2008;39:52–57.
    1. Ohnishi K. PML-RARalpha inhibitors (ATRA, tamibaroten, arsenic troxide) for acute promyelocytic leukemia. Int J Clin Oncol. 2007;12:313–317. doi: 10.1007/s10147-007-0694-6.
    1. Trus MR, Yang L, Suarez Saiz F, Bordeleau L, Jurisica I, Minden MD. The histone deacetylase inhibitor valproic acid alters sensitivity towards all trans retinoic acid in acute myeloblastic leukemia cells. Leukemia. 2005;19:1161–1168. doi: 10.1038/sj.leu.2403773.
    1. Bellos F, Mahlknecht U. Valproic acid and all-trans retinoic acid: meta-analysis of a palliative treatment regimen in AML and MDS patients. Onkologie. 2008;31:629–633.
    1. Bug G, Ritter M, Wassmann B, Schoch C, Heinzel T, Schwarz K, Romanski A, Kramer OH, Kampfmann M, Hoelzer D, Neubauer A, Ruthardt M, Ottmann OG. Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia. Cancer. 2005;104:2717–2725. doi: 10.1002/cncr.21589.
    1. Pilatrino C, Cilloni D, Messa E, Morotti A, Giugliano E, Pautasso M, Familiari U, Cappia S, Pelicci PG, Lo Coco F, Saglio G, Guerrasio A. Increase in platelet count in older, poor-risk patients with acute myeloid leukemia or myelodysplastic syndrome treated with valproic acid and all-trans retinoic acid. Cancer. 2005;104:101–109. doi: 10.1002/cncr.21132.
    1. Raffoux E, Chaibi P, Dombret H, Degos L. Valproic acid and all-trans retinoic acid for the treatment of elderly patients with acute myeloid leukemia. Haematologica. 2005;90:986–988.
    1. Ryningen A, Stapnes C, Lassalle P, Corbascio M, Gjertsen BT, Bruserud O. A subset of patients with high-risk acute myelogenous leukemia shows improved peripheral blood cell counts when treated with the combination of valproic acid, theophylline and all-trans retinoic acid. Leuk Res. 2009;33:779–787. doi: 10.1016/j.leukres.2008.10.005.
    1. Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, Löwenberg B, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Wijermans PW, Gore S, Greenberg PL. World Health Organization (WHO) international working group. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000;96:3671–3674.
    1. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108:419–425. doi: 10.1182/blood-2005-10-4149.
    1. Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Löwenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD. International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21:4642–4649. doi: 10.1200/JCO.2003.04.036.
    1. Fenaux P, Wang ZZ, Degos L. Treatment of acute promyelocytic leukemia by retinoids. Curr Top Microbiol Immunol. 2007;313:101–128. doi: 10.1007/978-3-540-34594-7_7.
    1. Patatanian E, Thompson DF. Retinoic acid syndrome: a review. J Clin Pharm Ther. 2008;33:331–338. doi: 10.1111/j.1365-2710.2008.00935.x.
    1. Lübbert M, Suciu S, Baila L, Rüter BH, Platzbecker U, Giagounidis A, Selleslag D, Labar B, Germing U, Salih HR, Beeldens F, Muus P, Pflüger KH, Coens C, Hagemeijer A, Eckart Schaefer H, Ganser A, Aul C, de Witte T, Wijermans PW. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol. 2011;29:1987–1996. doi: 10.1200/JCO.2010.30.9245.
    1. Cashen AF, Schiller GJ, O'Donnell MR, DiPersio JF. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol. 2010;28:556–561. doi: 10.1200/JCO.2009.23.9178.
    1. Garcia-Manero G. Demethylating agents in myeloid malignancies. Curr Opin Oncol. 2008;20:705–710. doi: 10.1097/CCO.0b013e328313699c.
    1. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach C, Silverman LR. International Vidaza High-Risk MDS Survival Study Group. 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;10:223–232. doi: 10.1016/S1470-2045(09)70003-8.
    1. Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, Sanz G, List AF, Gore S, Seymour JF, Dombret H, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010;28:562–569. doi: 10.1200/JCO.2009.23.8329.
    1. Lubbert M, Minden M. Decitabine in acute myeloid leukemia. Semin Hematol. 2005;42:S38–42.
    1. Blum W, Klisovic RB, Hackanson B, Liu Z, Liu S, Devine H, Vukosavljevic T, Huynh L, Lozanski G, Kefauver C, Plass C, Devine SM, Heerema NA, Murgo A, Chan KK, Grever MR, Byrd JC, Marcucci G. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol. 2007;25:3884–3891. doi: 10.1200/JCO.2006.09.4169.
    1. Raffoux E, Cras A, Recher C, Boëlle PY, de Labarthe A, Turlure P, Marolleau JP, Reman O, Gardin C, Victor M, Maury S, Rousselot P, Malfuson JV, Maarek O, Daniel MT, Fenaux P, Degos L, Chomienne C, Chevret S, Dombret H. Phase 2 clinical trial of 5-azacitidine, valproic acid, and all-trans retinoic acid in patients with high-risk acute myeloid leukemia or myelodysplastic syndrome. Oncotarget. 2010;1:34–42.
    1. Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F, Cortes J, Wierda WG, Ouzounian S, Quezada A, Pierce S, Estey EH, Issa JP, Kantarjian HM, Garcia-Manero G. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007;110:2302–2308. doi: 10.1182/blood-2007-03-078576.
    1. Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, Yang H, Rosner G, Verstovsek S, Rytting M, Wierda WG, Ravandi F, Koller C, Xiao L, Faderl S, Estrov Z, Cortes J, O'brien S, Estey E, Bueso-Ramos C, Fiorentino J, Jabbour E, Issa JP. Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia. Blood. 2006;108:3271–3279. doi: 10.1182/blood-2006-03-009142.
    1. Maslak P, Chanel S, Camacho LH, Soignet S, Pandolfi PP, Guernah I, Warrell R, Nimer S. Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia. 2006;20:212–217. doi: 10.1038/sj.leu.2404050.
    1. Wagner JM, Hackanson B, Lübbert M, Jung M. Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy. Clin Epigenetics. 2010;1:117–136. doi: 10.1007/s13148-010-0012-4.
    1. Tambaro FP, Dell'aversana C, Carafa V, Nebbioso A, Radic B, Ferrara F, Altucci L. Histone deacetylase inhibitors: clinical implications for hematological malignancies. Clin Epigenetics. 2010;1:25–44. doi: 10.1007/s13148-010-0006-2.
    1. Kadia TM, Yang H, Ferrajoli A, Maddipotti S, Schroeder C, Madden TL, Holleran JL, Egorin MJ, Ravandi F, Thomas DA, Newsome W, Sanchez-Gonzalez B, Zwiebel JA, Espinoza-Delgado I, Kantarjian HM, Garcia-Manero G. A phase I study of vorinostat in combination with idarubicin in relapsed or refractory leukaemia. Br J Haematol. 2010;150:72–82.
    1. Prebet T, Vey N. Vorinostat in acute myeloid leukemia and myelodysplastic syndromes. Expert Opin Investig Drugs. 2011;20:287–295. doi: 10.1517/13543784.2011.542750.
    1. Schaefer EW, Loaiza-Bonilla A, Juckett M, DiPersio JF, Roy V, Slack J, Wu W, Laumann K, Espinoza-Delgado I, Gore SD. Mayo P2C Phase II Consortium. A phase 2 study of vorinostat in acute myeloid leukemia. Haematologica. 2009;94:1375–1382. doi: 10.3324/haematol.2009.009217.
    1. Walter RB, Medeiros BC, Powell BL, Schiffer CA, Appelbaum FR, Estey EH. Phase II trial of vorinostat and gemtuzumab ozogamicin as induction and post-remission therapy in older adults with previously untreated acute myeloid leukemia. Haematologica. 2012;97:739–742. doi: 10.3324/haematol.2011.055822.
    1. Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, Wierda WG, Faderl S, Koller C, Morris G, Rosner G, Loboda A, Fantin VR, Randolph SS, Hardwick JS, Reilly JF, Chen C, Ricker JL, Secrist JP, Richon VM, Frankel SR, Kantarjian HM. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood. 2008;111:1060–1066.
    1. Berni Canani R, Di Costanzo M, Leone L. The epigenetic effects of butyrate: potential therapeutic implications for clinical practice. Clin Epigenetics. 2012;4:4. doi: 10.1186/1868-7083-4-4.
    1. Bruserud Ø, Stapnes C, Ersvaer E, Gjertsen BT, Ryningen A. Histone deacetylase inhibitors in cancer treatment: a review of the clinical toxicity and the modulation of gene expression in cancer cell. Curr Pharm Biotechnol. 2007;8:388–400. doi: 10.2174/138920107783018417.
    1. Bruserud Ø, Stapnes C, Tronstad KJ, Ryningen A, Anensen N, Gjertsen BT. Protein lysine acetylation in normal and leukaemic haematopoiesis: HDACs as possible therapeutic targets in adult AML. Expert Opin Ther Targets. 2006;10:51–68. doi: 10.1517/14728222.10.1.51.
    1. Hubeek I, Kaspers G-J L, Ossenkoppele GJ, Peters GJ. In: Deoxynucleoside Analogs in Cancer Therapy. Peters GJ, editor. Totowa, NJ: Humana Press; 2006. Cytosine arabinoside: metabolism, mechanisms of resistance and clinical pharmacology; pp. 119–152. [Teicher BA (Series Editor): Cancer Drug Discovery and Development.]
    1. Shipley JL, Butera JN. Acute myelogenous leukemia. Exp Hematol. 2009;37:649–658. doi: 10.1016/j.exphem.2009.04.002.
    1. Bolwell BJ, Cassileth PA, Gale RP. Low dose cytosine arabinoside in myelodysplasia and acute myelogenous leukemia: a review. Leukemia. 1987;1:575–579.
    1. Burnett AK, Hills RK, Hunter A, Milligan D, Kell J, Wheatley K, Yin J, McMullin MF, Cahalin P, Craig J, Bowen D, Russell N. The addition of arsenic trioxide to low-dose Ara-C in older patients with AML does not improve outcome. Leukemia. 2011;25:1122–1127. doi: 10.1038/leu.2011.59.
    1. Gu LF, Zhang WG, Wang FX, Cao XM, Chen YX, He AL, Liu J, Ma XR. Low dose of homoharringtonine and cytarabine combined with granulocyte colony-stimulating factor priming on the outcome of relapsed or refractory acute myeloid leukemia. J Cancer Res Clin Oncol. 2011;137:997–1003. doi: 10.1007/s00432-010-0947-z.
    1. Roboz GJ, Ritchie EK, Curcio T, Provenzano J, Carlin R, Samuel M, Wittenberg B, Mazumdar M, Christos PJ, Mathew S, Allen-Bard S, Feldman EJ. Arsenic trioxide and low-dose cytarabine in older patients with untreated acute myeloid leukemia, excluding acute promyelocytic leukemia. Cancer. 2008;113:2504–2511. doi: 10.1002/cncr.23855.
    1. Li JM, Shen Y, Wu DP, Liang H, Jin J, Chen FY, Song YP, Song EY, Qiu XF, Hou M, Qiu ZC, Shen ZX. Aclarubicin and low-dose Cytosine arabinoside in combination with granulocyte colony-stimulating factor in treating acute myeloid leukemia patients with relapsed or refractory disease and myelodysplastic syndrome: a multicenter study of 112 Chinese patients. Int J Hematol. 2005;82:48–54. doi: 10.1532/IJH97.A10424.
    1. Fredly H, Ersvaer E, Stapnes C, Gjertsen BT, Bruserud O. The combination of conventional chemotherapy with new targeted therapy in hematologic malignancies: the safety and efficiency of low-dose cytarabine supports its combination with new therapeutic agents in early clinical trials. Curr Cancer Ther Rev. 2009;5:243–255. doi: 10.2174/157339409789712645.
    1. Dingli D, Tefferi A. Hydroxyurea: The drug of choice for polycythemia vera and essential thrombocythemia. Curr Hematol Malig Rep. 2006;1:69–74. doi: 10.1007/s11899-006-0025-4.
    1. Saban N, Bujak M. Hydroxyurea and hydroxamic acid derivatives as antitumor drugs. Cancer Chemother Pharmacol. 2009;64:213–221. doi: 10.1007/s00280-009-0991-z.
    1. Latagliata R, Bongarzoni V, Carmosino I, Mengarelli A, Breccia M, Borza PA, D'Andrea M, D'Elia GM, Mecarocci S, Morano SG, Petti MC, Mandelli F, Alimena G. Acute myelogenous leukemia in elderly patients not eligible for intensive chemotherapy: the dark side of the moon. Ann Oncol. 2006;17:281–285.
    1. Burnett AK, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK, Wheatley K. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007;109:1114–1124. doi: 10.1002/cncr.22496.
    1. Petti MC, Tafuri A, Latagliata R, Aloe Spiriti MA, Montefusco E, Mancini M, Meloni G, Petrucci MT, Spadea A, Redi R, Alimena G, Mandelli F. High-dose hydroxyurea in the treatment of poor-risk myeloid leukemias. Ann Hematol. 2003;82:476–480. doi: 10.1007/s00277-003-0693-2.
    1. Karran P. Thiopurines, DNA damage, DNA repair and therapy-related cancer. Br Med Bull. 2006;79–80:153–170.
    1. Adam De Beaumais T, Jacqz-Aigrain E. Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia. Eur J Clin Pharmacol. 2012;68:1233–1242. doi: 10.1007/s00228-012-1251-4.
    1. Mori M, Ohta M, Miyata A, Higashihara M, Oshimi K, Kimura H, Yagasaki F, Sunami K. Treatment of acute myeloid leukemia patients aged more than 75 years: results of the E-AML-01 trial of the Japanese Elderly Leukemia and Lymphoma Study Group (JELLSG) Leuk Lymphoma. 2006;47:2062–2069. doi: 10.1080/10428190600733317.
    1. Miyawaki S, Sakamaki H, Ohtake S, Emi N, Yagasaki F, Mitani K, Matsuda S, Kishimoto Y, Miyazaki Y, Asou N, Matsushima T, Takahashi M, Ogawa Y, Honda S, Ohno R. Japan Adult Leukemia Study Group AML 97 Study. A randomized, postremission comparison of four courses of standard-dose consolidation therapy without maintenance therapy versus three courses of standard-dose consolidation with maintenance therapy in adults with acute myeloid leukemia: the Japan Adult Leukemia Study Group AML 97 Study. Cancer. 2005;104:2726–2734. doi: 10.1002/cncr.21493.
    1. Fredly H, Ersvaer E, Kittang AO, Tsykunova G, Gjertsen BT, Bruserud O. The combination of valproic acid, all-trans retinoic acid and low-dose cytarabine as disease-stabilizing treatment in acute myeloid leukemia. Clin Epigenetics. in press.
    1. Lane S, Gill D, McMillan NA, Saunders N, Murphy R, Spurr T, Keane C, Fan HM, Mollee P. Valproic acid combined with cytosine arabinoside in elderly patients with acute myeloid leukemia has in vitro but limited clinical activity. Leuk Lymphoma. 2012;53:1077–1083. doi: 10.3109/10428194.2011.642302.
    1. Bruserud O, Liseth K, Stamnesfet S, Cacic DL, Melve GK, Kristoffersen E, Hervig T, Reikvam H. Hyperleukocytosis and leukapheresis: a single centre experience with regard to apheresis technique and efficiency and a review of previous studies of leukapheresis in the treatment of acute myeloid leukemia. Transfus Med. in press.
    1. Cai D, Wang Y, Ottmann OG, Barth PJ, Neubauer A, Burchert A. FLT3-ITD-, but not BCR/ABL-transformed cells require concurrent Akt/mTor blockage to undergo apoptosis after histone deacetylase inhibitor treatment. Blood. 2006;107:2094–2097. doi: 10.1182/blood-2005-08-3317.
    1. Candelaria M, Herrera A, Labardini J, González-Fierro A, Trejo-Becerril C, Taja-Chayeb L, Pérez-Cárdenas E, de la Cruz-Hernández E, Arias-Bofill D, Vidal S, Cervera E, Dueñas-Gonzalez A. Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase-II trial. Ann Hematol. 2011;90:379–387. doi: 10.1007/s00277-010-1090-2.
    1. Chen J, Wang G, Wang L, Kang J, Wang J. Curcumin p38-dependently enhances the anticancer activity of valproic acid in human leukemia cells. Eur J Pharm Sci. 2010;41:210–218. doi: 10.1016/j.ejps.2010.06.011.
    1. Fabre C, Grosjean J, Tailler M, Boehrer S, Ades L, Perfettini JL, de Botton S, Fenaux P, Kroemer G. A novel effect of DNA methyltransferase and histone deacetylase inhibitors: NFkappaB inhibition in malignant myeloblasts. Cell Cycle. 2008;7:2139–2145. doi: 10.4161/cc.7.14.6268.
    1. Fuchs O, Provaznikova D, Marinov I, Kuzelova K, Spicka I. Antiproliferative and proapoptotic effects of proteasome inhibitors and their combination with histone deacetylase inhibitors on leukemia cells. Cardiovasc Hematol Disord Drug Targets. 2009;9:62–77. doi: 10.2174/187152909787581372.
    1. McCormack E, Haaland I, Venås G, Forthun RB, Huseby S, Gausdal G, Knappskog S, Micklem DR, Lorens JB, Bruserud O, Gjertsen BT. Synergistic induction of p53 mediated apoptosis by valproic acid and nutlin-3 in acute myeloid leukemia. Leukemia. 2012;26:910–917. doi: 10.1038/leu.2011.315.
    1. Nie D, Huang K, Yin S, Li Y, Xie S, Ma L, Wang X, Wu Y, Xiao J. Synergistic/additive interaction of valproic acid with bortezomib on proliferation and apoptosis of acute myeloid leukemia cells. Leuk Lymphoma. 2012;53:2487–2495. doi: 10.3109/10428194.2012.698273.
    1. Qi H, Ratnam M. Synergistic induction of folate receptor beta by all-trans retinoic acid and histone deacetylase inhibitors in acute myelogenous leukemia cells: mechanism and utility in enhancing selective growth inhibition by antifolates. Cancer Res. 2006;66:5875–5882. doi: 10.1158/0008-5472.CAN-05-4048.
    1. Ryningen A, Reikvam H, Nepstad I, Paulsen Rye K, Bruserud Ø. Inhibition of Mammalian target of rapamycin in human acute myeloid leukemia cells has diverse effects that depend on the environmental in vitro stress. Bone Marrow Res. 2012;2012:329061.
    1. Wang AH, Wei L, Chen L, Zhao SQ, Wu WL, Shen ZX, Li JM. Synergistic effect of bortezomib and valproic acid treatment on the proliferation and apoptosis of acute myeloid leukemia and myelodysplastic syndrome cells. Ann Hematol. 2011;90:917–931. doi: 10.1007/s00277-011-1175-6.
    1. Yu W, Wang J, Jin J, Qian W, Qian J, Cheng Y, Wang L. Heat shock protein 90 inhibition results in altered downstream signaling of mutant KIT and exerts synergistic effects on Kasumi-1 cells when combining with histone deacetylase inhibitor. Leuk Res. 2011;35:1212–1218. doi: 10.1016/j.leukres.2011.05.014.
    1. ten Cate B, Bremer E, de Bruyn M, Bijma T, Samplonius D, Schwemmlein M, Huls G, Fey G, Helfrich W. A novel AML-selective TRAIL fusion protein that is superior to Gemtuzumab Ozogamicin in terms of in vitro selectivity, activity and stability. Leukemia. 2009;23:1389–1397. doi: 10.1038/leu.2009.34.
    1. Ritchie EK, Roboz GJ. Levels of care: defining best supportive care in elderly patients with acute myeloid leukemia. Curr Hematol Malig Rep. 2010;5:95–100. doi: 10.1007/s11899-010-0048-8.
    1. Menzin J, Lang K, Earle CC, Kerney D, Mallick R. The outcomes and costs of acute myeloid leukemia among the elderly. Arch Intern Med. 2002;162:1597–1603. doi: 10.1001/archinte.162.14.1597.
    1. Deschler B, de Witte T, Mertelsmann R, Lübbert M. Treatment decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches. Haematologica. 2006;91:1513–1522.
    1. Greiner J, Döhner H, Schmitt M. Cancer vaccines for patients with acute myeloid leukemia–definition of leukemia-associated antigens and current clinical protocols targeting these antigens. Haematologica. 2006;91:1653–1661.
    1. Bruserud Ø, Ersvaer E, Olsnes A, Gjertsen BT. Anticancer immunotherapy in combination with proapoptotic therapy. Curr Cancer Drug Targets. 2008;8:666–675. doi: 10.2174/156800908786733496.
    1. Fredly H, Ersvær E, Gjertsen BT, Bruserud O. Immunogenic apoptosis in human acute myeloid leukemia (AML): primary human AML cells expose calreticulin and release heat shock protein (HSP) 70 and HSP90 during apoptosis. Oncol Rep. 2011;25:1549–1556.
    1. Flandrin P, Guyotat D, Duval A, Cornillon J, Tavernier E, Nadal N, Campos L. Significance of heat-shock protein (HSP) 90 expression in acute myeloid leukemia cells. Cell Stress Chaperones. 2008;13:357–364. doi: 10.1007/s12192-008-0035-3.
    1. Steiner K, Graf M, Hecht K, Reif S, Rossbacher L, Pfister K, Kolb HJ, Schmetzer HM, Multhoff G. High HSP70-membrane expression on leukemic cells from patients with acute myeloid leukemia is associated with a worse prognosis. Leukemia. 2006;20:2076–2079. doi: 10.1038/sj.leu.2404391.
    1. Thomas X, Campos L, Mounier C, Cornillon J, Flandrin P, Le QH, Piselli S, Guyotat D. Expression of heat-shock proteins is associated with major adverse prognostic factors in acute myeloid leukemia. Leuk Res. 2005;29:1049–1058. doi: 10.1016/j.leukres.2005.02.010.
    1. Yeh CH, Tseng R, Hannah A, Estrov Z, Estey E, Kantarjian H, Albitar M. Clinical correlation of circulating heat shock protein 70 in acute leukemia. Leuk Res. 2010;34:605–609. doi: 10.1016/j.leukres.2009.09.014.
    1. Liseth K, Ersvaer E, Hervig T, Bruserud Ø. Combination of intensive chemotherapy and anticancer vaccines in the treatment of human malignancies: the hematological experience. J Biomed Biotechnol. 2010;2010:692097.
    1. Alibhai SM, Leach M, Gupta V, Tomlinson GA, Brandwein JM, Saiz FS, Minden MD. Quality of life beyond 6 months after diagnosis in older adults with acute myeloid leukemia. Crit Rev Oncol Hematol. 2009;69:168–174. doi: 10.1016/j.critrevonc.2008.07.015.
    1. Redaelli A, Stephens JM, Brandt S, Botteman MF, Pashos CL. Short- and long-term effects of acute myeloid leukemia on patient health-related quality of life. Cancer Treat Rev. 2004;30:103–117. doi: 10.1016/S0305-7372(03)00142-7.
    1. Alibhai SM, Leach M, Kermalli H, Gupta V, Kowgier ME, Tomlinson GA, Brandwein J, Buckstein R, Minden MD. The impact of acute myeloid leukemia and its treatment on quality of life and functional status in older adults. Crit Rev Oncol Hematol. 2007;64:19–30. doi: 10.1016/j.critrevonc.2007.07.003.
    1. Sekeres MA, Stone RM, Zahrieh D, Neuberg D, Morrison V, De Angelo DJ, Galinsky I, Lee SJ. Decision-making and quality of life in older adults with acute myeloid leukemia or advanced myelodysplastic syndrome. Leukemia. 2004;18:809–816. doi: 10.1038/sj.leu.2403289.
    1. Wisløff F, Gulbrandsen N, Hjorth M, Lenhoff S, Fayers P. Quality of life may be affected more by disease parameters and response to therapy than by haemoglobin changes. Eur J Haematol. 2005;75:293–298. doi: 10.1111/j.1600-0609.2005.00509.x.
    1. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683–692. doi: 10.1016/j.cell.2007.01.029.
    1. Melnick AM. Epigenetics in AML. Best Pract Res Clin Haematol. 2010;23:463–468. doi: 10.1016/j.beha.2010.09.017.
    1. Jain N, Rossi A, Garcia-Manero G. Epigenetic therapy of leukemia: An update. Int J Biochem Cell Biol. 2009;41:72–80. doi: 10.1016/j.biocel.2008.10.006.
    1. Cameron EE, Bachman KE, Myöhänen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet. 1999;21:103–107. doi: 10.1038/5047.
    1. Fahrner JA, Eguchi S, Herman JG, Baylin SB. Dependence of histone modifications and gene expression on DNA hypermethylation in cancer. Cancer Res. 2002;62:7213–7218.
    1. Bennemann K, Galm O, Wilop S, Schubert C, Brummendorf TH, Jost E. Epigenetic dysregulation of secreted frizzled-related proteins in myeloproliferative neoplasms complements the JAK2V617F-mutation. Clin Epigenetics. 2012;4:12. doi: 10.1186/1868-7083-4-12.
    1. Mascarenhas J, Roper N, Chaurasia P, Hoffman R. Epigenetic abnormalities in myeloproliferative neoplasms: a target for novel therapeutic strategies. Clin Epigenetics. 2011;2:197–212. doi: 10.1007/s13148-011-0050-6.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner