title: Phase I study of azacitidine and bortezomib in adults with relapsed or refractory acute myeloid leukemia.
abstract: We previously reported that bortezomib indirectly modulates transcription of DNA methyltransferase 1 (DNMT). We designed a phase I study of azacitidine (a direct DNMT inhibitor) plus bortezomib in acute myeloid leukemia (AML) to determine safety and tolerability. Twenty-three adults with relapsed/refractory AML received azacitidine 75 mg/m(2) daily on days 1-7. Bortezomib was dose escalated from 0.7 mg/m(2) on days 2 and 5 to 1.3 mg/m(2) on days 2, 5, 9 and 12. The target dose was reached without dose limiting toxicities. Infection and/or febrile neutropenia were frequent. Patients received a median of 2 cycles of therapy (range, 1-12+). Five of 23 patients achieved remission, including two with morphologic and cytogenetic complete response (CR) and three with CR and incomplete count recovery (CRi). Of CR/CRi responders with cytogenetic abnormalities at baseline, three of four achieved cytogenetic CR. The combination of azacitidine and bortezomib was tolerable and active in this cohort of poor-risk previously treated patients with AML.
authors: Division of Hematology, Department of Internal Medicine.
authors: Alison R
authors: AR
authors: Walker
authors: Rebecca B
authors: RB
authors: Klisovic
authors: Ramiro
authors: R
authors: Garzon
authors: Larry J
authors: LJ
authors: Schaaf
authors: Kristina
authors: K
authors: Humphries
authors: Steven M
authors: SM
authors: Devine
authors: John C
authors: JC
authors: Byrd
authors: Michael R
authors: MR
authors: Grever
authors: Guido
authors: G
authors: Marcucci
authors: William
authors: W
authors: Blum
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage; D001853:Bone Marrow / Q000473:pathology; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D005260:Female; D006801:Humans; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011719:Pyrazines / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D001374:Azacitidine
keywords: Relapsed AML; azacitidine; bortezomib
references: N Engl J Med. 1999 Sep 30;341(14):1051-62
references: 10502596
references: Blood. 2012 Jun 21;119(25):6025-31
references: 22566605
references: Br J Haematol. 2009 Jun;145(5):598-605
references: 19344426
references: Nat Rev Cancer. 2012 Sep;12(9):599-612
references: 22898539
references: Blood. 2012 May 31;119(22):5229-38
references: 22517893
references: J Clin Oncol. 2005 Mar 20;23(9):1969-78
references: 15632409
references: Lancet Oncol. 2011 May;12(5):431-40
references: 21507715
references: J Clin Oncol. 2010 Feb 1;28(4):562-9
references: 20026804
references: Leuk Lymphoma. 2012 Jan;53(1):110-7
references: 21767242
references: Blood. 2004 Mar 1;103(5):1635-40
references: 14604977
references: Leuk Lymphoma. 2010 Jan;51(1):73-8
references: 20017599
references: Br J Haematol. 2009 Sep;146(6):652-5
references: 19624539
references: Leuk Lymphoma. 2002 Sep;43(9):1715-27
references: 12685823
references: Oncotarget. 2010 May;1(1):34-42
references: 21293051
references: Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7473-8
references: 20368434
references: Blood. 2008 Feb 15;111(4):2364-73
references: 18083845
references: J Clin Oncol. 2010 Feb 1;28(4):556-61
references: 20026803
references: Cancer Res. 2006 Jun 15;66(12):6361-9
references: 16778214
references: Cancer. 2006 Mar 1;106(5):1090-8
references: 16435386
references: J Clin Oncol. 2003 Dec 15;21(24):4642-9
references: 14673054
references: J Clin Oncol. 2009 Oct 20;27(30):5023-30
references: 19770386
references: Cancer. 2012 Feb 15;118(4):1014-22
references: 21761399
references: Blood. 2007 Oct 1;110(7):2302-8
references: 17596541
references: Cancer Res. 1970 Nov;30(11):2760-9
references: 5487063
references: Leukemia. 2013 Mar;27(3):725-8
references: 22828444
references: Blood. 2006 Nov 15;108(10):3271-9
references: 16882711
references: Cancer. 2008 Aug 15;113(4):765-71
references: 18543319
references: J Clin Oncol. 2007 Sep 1;25(25):3884-91
references: 17679729