Safety and efficacy of oral panobinostat plus chemotherapy in patients aged 65 years or younger with high-risk acute myeloid leukemia

• Published in: Leukemia research Vol. 85; p. 106197
• Main Authors: DeAngelo, Daniel J., Walker, Alison R., Schlenk, Richard F., Sierra, Jorge, Medeiros, Bruno C., Ocio, Enrique M., Röllig, Christoph, Strickland, Stephen A., Thol, Felicitas, Valera, Sue-zette, Dasgupta, Kohinoor, Berkowitz, Noah, Stuart, Robert K.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2019
• Subjects: Acute myeloid leukemia; Adolescent; Adult; Aged; AML; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cytarabine; Female; Humans; Idarubicin; Leukemia, Myeloid, Acute - diagnosis; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - mortality; Male; Middle Aged; Panobinostat; Panobinostat - administration & dosage; Panobinostat - pharmacokinetics; Treatment Outcome; Young Adult; Panobinostat; AML; Idarubicin; Cytarabine; Acute myeloid leukemia
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/j.leukres.2019.106197

•Novel therapeutic agents are needed for treatment of high-risk AML.•Panobinostat plus standard chemotherapy is safe and effective in high-risk AML.•The RP2D of panobinostat is 20 mg thrice/week in combo with idarubicin and ara-C.•This combo induced an ORR of 60.9% and 1-year event-free survival of 78%. The role of histone deacetylase inhibitors in the treatment of acute myeloid leukemia (AML) is not well characterized. The current study evaluated the safety and efficacy of panobinostat in combination with idarubicin and cytarabine in newly diagnosed patients aged ≤65 years with primary or secondary high-risk AML based on cytogenetic classification. Treatment included fixed dose idarubicin (12 mg/m2/d, IV; day 1–3) and cytarabine (100 mg/m2/d, continuous IV infusion; day 1–7) and escalating oral doses of panobinostat at 15 mg, 20 mg, and 25 mg, thrice weekly starting at week 2 of a 28-day cycle. Forty-six patients were enrolled (primary AML [n = 36], secondary AML [n = 10]). The median age was 55 years. The most common all-grade AEs were diarrhea (54.3%), nausea (39.1%), vomiting, and decreased appetite (each, 21.7%), stomatitis (19.6%), and fatigue (17.4%). The overall response rate was 60.9%, 43.5% achieved a complete remission (CR), and 17.4% achieved CR with incomplete count recovery. The event-free survival at 1-year was 78.3%. Panobinostat in combination with idarubicin and cytarabine demonstrated tolerable safety and efficacy in younger patients with high-risk AML. The recommended phase 2 dose of panobinostat in this combination was 20 mg. ClinicalTrials.gov registry no: NCT01242774, and European Trial Registry EudraCT no: 2009-016809-42.