Safety, pharmacokinetics, and pharmacodynamics of panobinostat in children, adolescents, and young adults with relapsed acute myeloid leukemia. Issue 21 (18th August 2020)

• Record Type: Journal Article
• Authors: Karol, Seth E.; Cooper, Todd M.; Mead, Paul E.; Crews, Kristine R.; Panetta, John C.; Alexander, Thomas B.; Taub, Jeffrey W.; Lacayo, Norman J.; Heym, Kenneth M.; Kuo, Dennis J.; Schiff, Deborah E.; Bhojwani, Deepa; Ge, Yubin; Klco, Jeffery M.; Ribeiro, Raul C.; Inaba, Hiroto; Pui, Ching‐Hon; Rubnitz, Jeffrey E.
• Is Part Of: Cancer. Volume 126:Issue 21(2020)
• Page Start: 4800
• Page End: 4805
• Publication Date: 2020-08-18
• Subjects: acute myeloid leukemia -- childhood -- relapse; Cancer -- Periodicals; Cancer -- Cytopathology -- Periodicals; 616.99405
• DOI: 10.1002/cncr.33156
• Languages: English
• ISSNs: 0008-543X

Abstract

Abstract : 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 2 ) before and in combination with fludarabine and cytarabine. 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. Abstract : The combination of panobinostat with fludarabine and cytarabine is safe and active in children with relapsed acute myeloid leukemia (AML). Panobinostat results in increased histone acetylation in leukemic blasts of children with relapsed AML.