TY - JOUR
T1 - A phase i study of vorinostat in combination with idarubicin in relapsed or refractory leukaemia
T2 - Research paper
AU - Kadia, Tapan M.
AU - Yang, Hui
AU - Ferrajoli, Alessandra
AU - Maddipotti, Sirisha
AU - Schroeder, Claudia
AU - Madden, Timothy L.
AU - Holleran, Julianne L.
AU - Egorin, Merrill J.
AU - Ravandi, Farhad
AU - Thomas, Deborah A.
AU - Newsome, Willie
AU - Sanchez-Gonzalez, Blanca
AU - Zwiebel, James A.
AU - Espinoza-Delgado, Igor
AU - Kantarjian, Hagop M.
AU - Garcia-Manero, Guillermo
PY - 2010/7
Y1 - 2010/7
N2 - 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 (2·5%), 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.
AB - 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 (2·5%), 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.
KW - Epigenetics
KW - Histone
KW - Idarubicin
KW - Leukaemia
KW - Vorinostat
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U2 - 10.1111/j.1365-2141.2010.08211.x
DO - 10.1111/j.1365-2141.2010.08211.x
M3 - Article
C2 - 20456355
AN - SCOPUS:77953487591
SN - 0007-1048
VL - 150
SP - 72
EP - 82
JO - British Journal of Haematology
JF - British Journal of Haematology
IS - 1
ER -