Safety, pharmacokinetics, and pharmacodynamics of panobinostat in children, adolescents, and young adults with relapsed acute myeloid leukemia.
acute myeloid leukemia
childhood
relapse
Journal
Cancer
ISSN: 1097-0142
Titre abrégé: Cancer
Pays: United States
ID NLM: 0374236
Informations de publication
Date de publication:
01 11 2020
01 11 2020
Historique:
received:
17
05
2020
revised:
09
07
2020
accepted:
24
07
2020
pubmed:
19
8
2020
medline:
12
6
2021
entrez:
19
8
2020
Statut:
ppublish
Résumé
Novel therapies are urgently needed for pediatric patients with relapsed acute myeloid leukemia (AML). To determine whether the histone deacetylase inhibitor panobinostat could be safely given in combination with intensive chemotherapy, a phase 1 trial was performed in which 17 pediatric patients with relapsed or refractory AML received panobinostat (10, 15, or 20 mg/m All dose levels were tolerated, with no dose-limiting toxicities observed at any dose level. Pharmacokinetic studies demonstrated that exposure to panobinostat was proportional to the dose given, with no associations between pharmacokinetic parameters and age, weight, or body surface area. Among the 9 patients who had sufficient (>2%) circulating blasts on which histone acetylation studies could be performed, 7 demonstrated at least 1.5-fold increases in acetylation. Although no patients had a decrease in circulating blasts after single-agent panobinostat, 8 of the 17 patients (47%), including 5 of the 6 patients treated at dose level 3, achieved complete remission. Among the 8 complete responders, 6 (75%) attained negative minimal residual disease status. Panobinostat can be safely administered with chemotherapy and results in increased blast histone acetylation. This suggests that it should be further studied in AML.
Sections du résumé
BACKGROUND
Novel therapies are urgently needed for pediatric patients with relapsed acute myeloid leukemia (AML).
METHODS
To determine whether the histone deacetylase inhibitor panobinostat could be safely given in combination with intensive chemotherapy, a phase 1 trial was performed in which 17 pediatric patients with relapsed or refractory AML received panobinostat (10, 15, or 20 mg/m
RESULTS
All dose levels were tolerated, with no dose-limiting toxicities observed at any dose level. Pharmacokinetic studies demonstrated that exposure to panobinostat was proportional to the dose given, with no associations between pharmacokinetic parameters and age, weight, or body surface area. Among the 9 patients who had sufficient (>2%) circulating blasts on which histone acetylation studies could be performed, 7 demonstrated at least 1.5-fold increases in acetylation. Although no patients had a decrease in circulating blasts after single-agent panobinostat, 8 of the 17 patients (47%), including 5 of the 6 patients treated at dose level 3, achieved complete remission. Among the 8 complete responders, 6 (75%) attained negative minimal residual disease status.
CONCLUSIONS
Panobinostat can be safely administered with chemotherapy and results in increased blast histone acetylation. This suggests that it should be further studied in AML.
Identifiants
pubmed: 32809242
doi: 10.1002/cncr.33156
pmc: PMC7722063
mid: NIHMS1629149
doi:
Substances chimiques
Panobinostat
9647FM7Y3Z
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4800-4805Subventions
Organisme : NCI NIH HHS
ID : K12 CA120780
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA021765
Pays : United States
Organisme : NCI NIH HHS
ID : CA021765
Pays : United States
Informations de copyright
© 2020 American Cancer Society.
Références
Haematologica. 2016 Mar;101(3):269-78
pubmed: 26928248
Invest New Drugs. 2012 Jun;30(3):1096-106
pubmed: 21484248
J Clin Oncol. 2012 Jun 20;30(18):2204-10
pubmed: 22585696
PLoS One. 2011 Feb 16;6(2):e17138
pubmed: 21359182
J Clin Oncol. 2003 Dec 15;21(24):4642-9
pubmed: 14673054
Cytometry A. 2014 Jan;85(1):78-87
pubmed: 24038859
Clin Cancer Res. 2019 Aug 15;25(16):4917-4923
pubmed: 31152020
J Clin Oncol. 2008 Jan 10;26(2):190-5
pubmed: 18182661
PLoS One. 2013 Nov 11;8(11):e79106
pubmed: 24244429
Blood Cancer J. 2014 Jan 10;4:e170
pubmed: 24413064
Cancer Chemother Pharmacol. 2010 May;66(1):181-9
pubmed: 20217089
J Clin Oncol. 2013 Feb 10;31(5):599-607
pubmed: 23319696
Eur J Clin Pharmacol. 2015 Jun;71(6):663-672
pubmed: 25939707
Cancer Chemother Pharmacol. 2012 Oct;70(4):513-22
pubmed: 22864948