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 - Tập 110 - Trang 2302-2308 - 2007
Andres O. Soriano1, Hui Yang1, Stefan Faderl1, Zeev Estrov, Francis Giles1, Farhad Ravandi1, Jorge Cortes1, William G. Wierda1, Souzanne Ouzounian1, Andres Quezada1, Sherry Pierce1, Elihu H. Estey1, Jean-Pierre J. Issa1, Hagop M. Kantarjian1, Guillermo Garcia-Manero1
1Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX

Tóm tắt

The combination of a DNA hypomethylating agent with a histone deacetylase inhibitor has synergistic antileukemia activity and may restore sensitivity to all-trans retinoic acid (ATRA). We conducted a phase 1/2 study of the combination of 5-azacitidine (5-AZA), valproic acid (VPA), and ATRA in patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. 5-AZA was administered subcutaneously at a fixed dose of 75 mg/m2 daily for 7 days. VPA was dose-escalated and given orally daily for 7 days concomitantly with 5-AZA. ATRA was given at 45 mg/m2 orally daily for 5 days, starting on day 3. A total of 53 patients were treated. Their median age was 69 years (range, 5-84 years). The maximum tolerated dose of VPA in this combination was 50 mg/kg daily for 7 days. Dose-limiting toxicity was reversible neurotoxicity. The overall response rate was 42%. In previously untreated older patients, the response rate was 52%. Median number of courses to response was 1 (range, 1-3 courses). Median remission duration was 26 weeks, and median survival has not been reached. A significant decrease in global DNA methylation and induction of histone acetylation were achieved. VPA blood levels were higher in responders (P < .005). In conclusion, the combination studied is safe and has significant clinical activity. This clinical trial was registered at www.clinicaltrials.gov as no. NCT00326170.

Tài liệu tham khảo

Silverman, 2002, Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B., J Clin Oncol, 20, 2429, 10.1200/JCO.2002.04.117 Sudan, 2006, Treatment of acute myelogenous leukemia with outpatient azacitidine., Cancer, 107, 1839, 10.1002/cncr.22204 Silverman, 2006, 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, 24, 3895, 10.1200/JCO.2005.05.4346 Bhalla, 2005, Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies., J Clin Oncol, 23, 3971, 10.1200/JCO.2005.16.600 Goffin, 2002, DNA methyltransferase inhibitors: state of the art., Ann Oncol, 13, 1699, 10.1093/annonc/mdf314 Herman, 2003, Gene silencing in cancer in association with promoter hypermethylation., N Engl J Med, 349, 2042, 10.1056/NEJMra023075 Issa, 1997, DNA methylation changes in hematologic malignancies: biologic and clinical implications., Leukemia, 11, S7 Marks, 2001, Histone deacetylases and cancer: causes and therapies., Nat Rev Cancer, 1, 194, 10.1038/35106079 Yang, 2005, Antileukemia activity of the combination of 5-aza-2′-deoxycytidine with valproic acid., Leuk Res, 29, 739, 10.1016/j.leukres.2004.11.022 Garcia-Manero, 2005, Future directions for the use of hypomethylating agents., Semin Hematol, 42, S50, 10.1053/j.seminhematol.2005.05.004 Phiel, 2001, Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen., J Biol Chem, 276, 36734, 10.1074/jbc.M101287200 Johannessen, 2003, Valproate: past, present, and future., CNS Drug Rev, 9, 199, 10.1111/j.1527-3458.2003.tb00249.x Gottlicher, 2001, Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells., EMBO J, 20, 6969, 10.1093/emboj/20.24.6969 Kuendgen, 2004, Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid., Blood, 104, 1266, 10.1182/blood-2003-12-4333 Kuendgen, 2006, The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia., Cancer, 106, 112, 10.1002/cncr.21552 Garcia-Manero, 2006, Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia., Blood, 108, 3271, 10.1182/blood-2006-03-009142 Appelbaum, 2000, NCCN practice guidelines for acute myelogenous leukemia., Oncology (Huntingt), 14, 53 Estey, 1999, Randomized phase II study of fludarabine + cytosine arabinoside + idarubicin ± all-trans retinoic acid ± granulocyte colony-stimulating factor in poor prognosis newly diagnosed acute myeloid leukemia and myelodysplastic syndrome., Blood, 93, 2478, 10.1182/blood.V93.8.2478 Alimena, 1988, Interferon alpha-2b as therapy for Ph-positive chronic myelogenous leukemia: a study of 82 patients treated with intermittent or daily administration., Blood, 72, 642, 10.1182/blood.V72.2.642.642 Di Croce, 2002, Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor., Science, 295, 1079, 10.1126/science.1065173 Yang, 2004, A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements., Nucleic Acids Res, 32, e38, 10.1093/nar/gnh032 Davis, 1994, Valproic acid: a reappraisal of its pharmacological properties and clinical efficacy in epilepsy., Drugs, 47, 332, 10.2165/00003495-199447020-00008 Dreifuss, 1987, Valproic acid hepatic fatalities: a retrospective review., Neurology, 37, 379, 10.1212/WNL.37.3.379 Driever, 1999, Valproic acid for the treatment of pediatric malignant glioma., Klin Padiatr, 211, 323, 10.1055/s-2008-1043809 Garcia-Manero, 2005, Final results of a phase I study of the histone deacetylase inhibitor vorinostat (suberoyanilide hydroxamic acid, SAHA), in patients with leukemia and myelodysplastic syndrome [abstract]., Blood, 106, 785a, 10.1182/blood.V106.11.4639.4639 Maslak, 2006, Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome., Leukemia, 20, 212, 10.1038/sj.leu.2404050 Gore, 2006, Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms., Cancer Res, 66, 6361, 10.1158/0008-5472.CAN-06-0080 Pilatrino, 2005, 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, 104, 101, 10.1002/cncr.21132 Raffoux, 2005, Valproic acid and all-trans retinoic acid for the treatment of elderly patients with acute myeloid leukemia., Haematologica, 90, 986 Garcia-Manero, 2006, Phase I/II study of the oral isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 in combination with azacitidine in patients (pts) with high-risk myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) [abstract]., Blood, 108, 552a, 10.1182/blood.V108.11.1954.1954 Youssef, 2004, Hypermethylation and silencing of the putative tumor suppressor Tazarotene-induced gene 1 in human cancers., Cancer Res, 64, 2411, 10.1158/0008-5472.CAN-03-0164 Trus, 2005, The histone deacetylase inhibitor valproic acid alters sensitivity towards all trans retinoic acid in acute myeloblastic leukemia cells., Leukemia, 19, 1161, 10.1038/sj.leu.2403773 Cimino, 2006, Sequential valproic acid/all-trans retinoic acid treatment reprograms differentiation in refractory and high-risk acute myeloid leukemia., Cancer Res, 66, 8903, 10.1158/0008-5472.CAN-05-2726 Cameron, 1999, Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer., Nat Genet, 21, 103, 10.1038/5047