Seth E Karol1,2, Todd M Cooper3, Paul E Mead1, Kristine R Crews1, John C Panetta1, Thomas B Alexander4, Jeffrey W Taub5, Norman J Lacayo6,7, Kenneth M Heym8, Dennis J Kuo9,10, Deborah E Schiff9,10, Deepa Bhojwani11, Yubin Ge5, Jeffery M Klco1,2, Raul C Ribeiro1,2, Hiroto Inaba1,2, Ching-Hon Pui1,2, Jeffrey E Rubnitz1,2. 1. St. Jude Children's Research Hospital, Memphis, Tennessee. 2. College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee. 3. Seattle Children's Hospital, Seattle, Washington. 4. University of North Carolina, Chapel Hill, North Carolina. 5. Children's Hospital of Michigan, Detroit, Michigan. 6. Lucile Packard Children's Hospital, Palo Alto, California. 7. Stanford Cancer Center, Palo Alto, California. 8. Cook Children's Medical Center, Fort Worth, Texas. 9. Rady Children's Hospital, San Diego, California. 10. University of California San Diego School of Medicine, La Jolla, California. 11. Children's Hospital of Los Angeles, Los Angeles, California.
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/m2 ) 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.
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/m2 ) 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.
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