title: Phase I study of bortezomib in refractory or relapsed acute leukemias.
abstract: Bortezomib (Velcade, formerly PS-341) is proteasome inhibitor with documented antitumor activity in multiple myeloma and other lymphoid malignancies. We performed a Phase I study to investigate the maximum tolerated dose and dose-limiting toxicity of bortezomib in patients with acute leukemias refractory to or relapsing after prior therapy. Fifteen patients were treated with 0.75 (n = 3), 1.25 (n = 7), or 1.5 (n = 5) mg/m(2) bortezomib administered twice weekly for 4 weeks every 6 weeks. Dose-limiting toxicity included orthostatic hypotension (n = 2), nausea (n = 2), diarrhea (n = 1), and fluid retention (n = 1), all at 1.5 mg/m(2) bortezomib. Proteasome inhibition was dose dependent and reached 68% at 1.5 mg/m(2) bortezomib. Peak inhibition was observed 1 h after treatment and returned to near baseline levels by 72 h after treatment. Incubation of blast cells with bortezomib in vitro showed induction of apoptosis in three of five patients investigated. We conclude that the maximum tolerated dose of bortezomib in patients with acute leukemia is 1.25 mg/m(2), using a twice-weekly for 4 weeks every 6 weeks schedule. The in vitro evidence of antileukemia and transient hematological improvements observed in some patients warrants further investigation of bortezomib in acute leukemias, probably in combination with other agents.
authors.affiliation: Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. jcortes@mdanderson.org
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Deborah
authors.initials: D
authors.lastname: Thomas
authors.forename: Charles
authors.initials: C
authors.lastname: Koller
authors.forename: Francis
authors.initials: F
authors.lastname: Giles
authors.forename: Elihu
authors.initials: E
authors.lastname: Estey
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: David
authors.initials: D
authors.lastname: McConkey
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Ruiz
authors.forename: Gira
authors.initials: G
authors.lastname: Patel
authors.forename: Roberto
authors.initials: R
authors.lastname: Guerciolini
authors.forename: John
authors.initials: J
authors.lastname: Wright
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008956:Models, Chemical; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000627:therapeutic use*; D012008:Recurrence; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex