A phase I study of vorinostat in combination with idarubicin in relapsed or refractory leukaemia

作者：Kadia Tapan M; Yang Hui; Ferrajoli Alessandra; Maddipotti Sirisha; Schroeder Claudia; Madden Timothy L; Holleran Julianne L; Egorin Merrill J; Ravandi Farhad; Thomas Deborah A; Newsome Willie; Sanchez Gonzalez Blanca; Zwiebel James A; Espinoza Delgado Igor; Kantarjian Hagop M; Garcia Manero Guillermo^*

来源：British Journal of Haematology, 2010, 150(1): 72-82.

DOI：10.1111/j.1365-2141.2010.08211.x

• vorinostat
• idarubicin
• leukaemia
• histone
• epigenetics

P>Histone deacetylase inhibitors (HDACi) affect chromatin remodelling and modulate the expression of aberrantly silenced genes. HDACi have single-agent clinical activity in haematological malignancies and have synergistic anti-leukaemia activity when combined with anthracyclines in vitro. We conducted a two-arm, parallel Phase I trial to investigate two schedules of escalating doses of vorinostat (Schedule A: thrice daily (TID) for 14 d; B: TID for 3 d) in combination with a fixed dose of idarubicin in patients with refractory leukaemia. Of the 41 patients enrolled, 90% had acute myeloid leukaemia, with a median of 3 prior therapies. Seven responses (17%) were documented (two complete response (5%), one complete response without platelet recovery (2 center dot 5%), and four marrow responses). The 3-d schedule of vorinostat was better tolerated than the 14-d schedule. The maximum tolerated dose for vorinostat was defined as 400 mg TID for 3 d. The most common grade 3 and 4 toxicities included mucositis, fatigue and diarrhoea. Correlative studies demonstrated histone acetylation in patients on therapy and modulation of CDKN1A and TOP2A (topoisomerase II) gene expression. Pharmacokinetic analysis confirmed a dose-related elevation in plasma vorinostat concentrations. The combination of vorinostat and idarubicin is generally tolerable and active in patients with advanced leukaemia and should be studied in the front-line setting.

• 出版日期2010-7