Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome

Peter Tan, Andrew Wei, Sridurga Mithraprabhu, Nicholas James Cummings, Hong Bin Liu, Michelle Perugini, Kerry D Reed, Sharon Avery, Sushrut Patil, Patricia Ann Walker, Peter N Mollee, Andrew P Grigg, Richard J D'Andrea, Anthony Edwin Dear, Andrew Spencer

Research output: Contribution to journalArticleResearchpeer-review

73 Citations (Scopus)

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) naive to intensive chemotherapy. Thirty-nine patients (AML=29, MDS=10) received azacitidine 75 mg/m2 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.
Original languageEnglish
Article numbere170
Pages (from-to)1 - 8
Number of pages8
JournalBlood Cancer Journal
Volume4
Issue number1
DOIs
Publication statusPublished - 2014

Cite this

Tan, P., Wei, A., Mithraprabhu, S., Cummings, N. J., Liu, H. B., Perugini, M., Reed, K. D., Avery, S., Patil, S., Walker, P. A., Mollee, P. N., Grigg, A. P., D'Andrea, R. J., Dear, A. E., & Spencer, A. (2014). Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood Cancer Journal, 4(1), 1 - 8. [e170]. https://doi.org/10.1038/bcj.2013.68