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Title: Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome.
Austin Authors: Tan, P;Wei, A;Mithraprabhu, S;Cummings, N;Liu, H B;Perugini, M;Reed, K;Avery, S;Patil, S;Walker, P;Mollee, P;Grigg, Andrew P ;D'Andrea, R;Dear, A;Spencer, A
Affiliation: Australian Centre for Blood Diseases, Biotechnology Division, Eastern Clinical Research Unit, Monash University, Melbourne, Victoria, Australia
Department of Haematology, Austin Hospital, Melbourne, Victoria, Australia
Division of Cancer Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia
Institute of Medical and Veterinary Science, Department of Haematology and Centre for Cancer Biology, Adelaide, South Australia, Australia
Department of Clinical Haematology, Alfred Hospital, Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia
Issue Date: 10-Jan-2014
Publication information: Blood Cancer Journal 2014; 4(): e170
Abstract: Therapeutic options are limited for elderly patients with acute myeloid leukemia (AML). A phase Ib/II study was undertaken to evaluate the maximum-tolerated dose (MTD) and preliminary efficacy of the pan-histone deacetylase inhibitor panobinostat (LBH589) in combination with azacitidine in patients with AML or high-risk myelodysplastic syndrome (MDS) naïve to intensive chemotherapy. Thirty-nine patients (AML=29, MDS=10) received azacitidine 75 mg/m(2) subcutaneously (days 1-5) and oral panobinostat (starting on day 5, thrice weekly for seven doses) in 28-day cycles until toxicity or disease progression. Dose-limiting toxicities during the phase Ib stage were observed in 0/4 patients receiving 10 mg panobinostat, in 1/7 patients (fatigue) receiving 20 mg, in 1/6 patients (fatigue) receiving 30 mg and in 4/5 patients (fatigue, syncope, hyponatremia and somnolence) receiving 40 mg. In phase II, an additional 17 patients received panobinostat at a MTD of 30 mg. The overall response rate (ORR=CR+CRi+PR) in patients with AML was 31% (9/29) and that in patients with MDS was 50% (5/10). After a median follow-up of 13 months, the median overall survival was 8 and 16 months in patients with AML and MDS, respectively. Increased histone H3 and H4 acetylation was a useful early biomarker of clinical response. Combining panobinostat with azacitidine was tolerable and clinically active in high-risk MDS/AML patients, warranting further exploration.
Gov't Doc #: 24413064
DOI: 10.1038/bcj.2013.68
Journal: Blood cancer journal
Type: Journal Article
Appears in Collections:Journal articles

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