title: A Phase 2 study of bortezomib combined with either idarubicin/cytarabine or cytarabine/etoposide in children with relapsed, refractory or secondary acute myeloid leukemia: a report from the Children's Oncology Group.
abstract: BACKGROUND
  This Phase 2 study tested the tolerability and efficacy of bortezomib combined with reinduction chemotherapy for pediatric patients with relapsed, refractory or secondary acute myeloid leukemia (AML). Correlative studies measured putative AML leukemia initiating cells (AML-LIC) before and after treatment.
  
  
  METHODS
  Patients with <400 mg/m(2) prior anthracycline received bortezomib combined with idarubicin (12 mg/m(2) days 1-3) and low-dose cytarabine (100 mg/m(2) days 1-7) (Arm A). Patients with ≥400 mg/m(2) prior anthracycline received bortezomib with etoposide (100 mg/m(2) on days 1-5) and high-dose cytarabine (1 g/m(2) every 12 hours for 10 doses) (Arm B).
  
  
  RESULTS
  Forty-six patients were treated with 58 bortezomib-containing cycles. The dose finding phase of Arm B established the recommended Phase 2 dose of bortezomib at 1.3 mg/m(2) on days 1, 4, and 8 with Arm B chemotherapy. Both arms were closed after failure to meet predetermined efficacy thresholds during the first stage of the two-stage design. The complete response (CR + CRp) rates were 29% for Arm A and 43% for Arm B. Counting additional CRi responses (CR with incomplete neutrophil recovery), the overall CR rates were 57% for Arm A and 48% for Arm B. The 2-year overall survival (OS) was 39 ± 15%. Correlative studies showed that LIC depletion after the first cycle was associated with clinical response.
  
  
  CONCLUSIONS
  Bortezomib is tolerable when added to chemotherapy regimens for relapsed pediatric AML, but the regimens did not exceed preset minimum response criteria to allow continued accrual. This study also suggests that AML-LIC depletion has prognostic value.
authors: Texas Children's Cancer and Hematology Centers at Baylor College of Medicine, Houston, Texas.
authors: Terzah M
authors: TM
authors: Horton
authors: John P
authors: JP
authors: Perentesis
authors: Alan S
authors: AS
authors: Gamis
authors: Todd A
authors: TA
authors: Alonzo
authors: Robert B
authors: RB
authors: Gerbing
authors: Jennifer
authors: J
authors: Ballard
authors: Kathleen
authors: K
authors: Adlard
authors: Dianna S
authors: DS
authors: Howard
authors: Franklin O
authors: FO
authors: Smith
authors: Gaye
authors: G
authors: Jenkins
authors: Angelé
authors: A
authors: Kelder
authors: Gerrit J
authors: GJ
authors: Schuurhuis
authors: Jeffrey A
authors: JA
authors: Moscow
mesh_terms: D000293:Adolescent; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage / Q000009:adverse effects; D007223:Infant; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D011817:Rabbits; D016879:Salvage Therapy / Q000379:methods; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D003561:Cytarabine; D000069286:Bortezomib; D005047:Etoposide; D015255:Idarubicin
keywords: AML; AraC; Velcade; pediatric oncology; relapse