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

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, Peter ; Wei, Andrew ; Mithraprabhu, Sridurga ; Cummings, Nicholas James ; Liu, Hong Bin ; Perugini, Michelle ; Reed, Kerry D ; Avery, Sharon ; Patil, Sushrut ; Walker, Patricia Ann ; Mollee, Peter N ; Grigg, Andrew P ; D'Andrea, Richard J ; Dear, Anthony Edwin ; Spencer, Andrew. / Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome. In: Blood Cancer Journal. 2014 ; Vol. 4, No. 1. pp. 1 - 8.
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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.",
author = "Peter Tan and Andrew Wei and Sridurga Mithraprabhu and Cummings, {Nicholas James} and Liu, {Hong Bin} and Michelle Perugini and Reed, {Kerry D} and Sharon Avery and Sushrut Patil and Walker, {Patricia Ann} and Mollee, {Peter N} and Grigg, {Andrew P} and D'Andrea, {Richard J} and Dear, {Anthony Edwin} and Andrew Spencer",
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Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome. / Tan, Peter; Wei, Andrew; Mithraprabhu, Sridurga; Cummings, Nicholas James; Liu, Hong Bin; Perugini, Michelle; Reed, Kerry D; Avery, Sharon; Patil, Sushrut; Walker, Patricia Ann; Mollee, Peter N; Grigg, Andrew P; D'Andrea, Richard J; Dear, Anthony Edwin; Spencer, Andrew.

In: Blood Cancer Journal, Vol. 4, No. 1, e170, 2014, p. 1 - 8.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome

AU - Tan, Peter

AU - Wei, Andrew

AU - Mithraprabhu, Sridurga

AU - Cummings, Nicholas James

AU - Liu, Hong Bin

AU - Perugini, Michelle

AU - Reed, Kerry D

AU - Avery, Sharon

AU - Patil, Sushrut

AU - Walker, Patricia Ann

AU - Mollee, Peter N

AU - Grigg, Andrew P

AU - D'Andrea, Richard J

AU - Dear, Anthony Edwin

AU - Spencer, Andrew

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AB - 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.

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