title: Phase I and pharmacokinetic study of bortezomib in combination with idarubicin and cytarabine in patients with acute myelogenous leukemia.
abstract: OBJECTIVE
  Proteasome inhibition results in cytotoxicity to the leukemia stem cell in vitro. We conducted this phase I study to determine if the proteasome inhibitor bortezomib could be safely added to induction chemotherapy in patients with acute myelogenous leukemia (AML).
  
  
  METHODS
  Bortezomib was given on days 1, 4, 8, and 11 at doses of 0.7, 1.0, 1.3, or 1.5 mg/m(2) with idarubicin 12 mg/m(2) on days 1 to 3 and cytarabine 100 mg/m(2)/day on days 1 to 7.
  
  
  RESULTS
  A total of 31 patients were enrolled. The median age was 62 years, and 16 patients were male. Nine patients had relapsed AML (ages, 18-59 years, n = 4 and > or = 60 years, n = 5). There were 22 patients of > or = 60 years with previously untreated AML (eight with prior myelodysplasia/myeloproliferative disorder or cytotoxic therapy). All doses of bortezomib, up to and including 1.5 mg/m(2), were tolerable. Nonhematologic grade 3 or greater toxicities included 12 hypoxia (38%; 11 were grade 3), 4 hyperbilirubinemia (13%), and 6 elevated aspartate aminotransferase (19%). Overall, 19 patients (61%) achieved complete remission (CR) and three had CR with incomplete platelet recovery. Pharmacokinetic studies revealed that the total body clearance of bortezomib decreased significantly (P < 0.01, N = 26) between the first (mean +/- SD, 41.9 +/- 17.1 L/h/m(2)) and third (18.4 +/- 7.0 L/h/m(2)) doses. Increased bone marrow expression of CD74 was associated with CR.
  
  
  CONCLUSIONS
  The combination of bortezomib, idarubicin, and cytarabine showed a good safety profile. The recommended dose of bortezomib for phase II studies with idarubicin and cytarabine is 1.5 mg/m(2).
authors.affiliation: Hematology/Oncology Unit, Massachusetts General Hospital, Boston, MA 02114, USA. eattar@partners.org
authors.forename: Eyal C
authors.initials: EC
authors.lastname: Attar
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: De Angelo
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.forename: Ferdinando
authors.initials: F
authors.lastname: D'Amato
authors.forename: David
authors.initials: D
authors.lastname: Zahrieh
authors.forename: Andres
authors.initials: A
authors.lastname: Sirulnik
authors.forename: Martha
authors.initials: M
authors.lastname: Wadleigh
authors.forename: Karen K
authors.initials: KK
authors.lastname: Ballen
authors.forename: Steve
authors.initials: S
authors.lastname: McAfee
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Miller
authors.forename: James
authors.initials: J
authors.lastname: Levine
authors.forename: Ilene
authors.initials: I
authors.lastname: Galinsky
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Trehu
authors.forename: David
authors.initials: D
authors.lastname: Schenkein
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.forename: Philip C
authors.initials: PC
authors.lastname: Amrein
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics*; D014408:Biomarkers, Tumor; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D015331:Cohort Studies; D003561:Cytarabine / Q000008:administration & dosage; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D020411:Oligonucleotide Array Sequence Analysis; D011719:Pyrazines / Q000008:administration & dosage; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D001897:Boronic Acids; D011719:Pyrazines; D003561:Cytarabine; D000069286:Bortezomib; D015255:Idarubicin