title: Phase I study of bortezomib combined with chemotherapy in children with relapsed childhood acute lymphoblastic leukemia (ALL): a report from the therapeutic advances in childhood leukemia (TACL) consortium.
abstract: BACKGROUND
  Outcomes remain poor for children after relapse of acute lymphoblastic leukemia (ALL), especially after early marrow relapse. Bortezomib is a proteasome inhibitor with in vitro synergy with corticosteroids and clinical activity in human lymphoid malignancies.
  
  
  METHODS
  This is a Phase I study of escalating doses bortezomib administered days 1, 4, 8, and 11, added to 4-drug induction chemotherapy with vincristine, dexamethasone, pegylated L-asparaginase, and doxorubicin (VXLD) in children with relapsed ALL.
  
  
  RESULTS
  Ten patients were enrolled, five in first marrow relapse, and five in second relapse. Four patients were enrolled at dose level 1 (bortezomib 1 mg/m(2)). One patient was not evaluable for toxicity because of omitted dexamethasone doses. No dose-limiting toxicity (DLT) was observed. Six patients were enrolled at dose level 2 (bortezomib 1.3 mg/m(2)). One patient had dose-limiting hypophosphatemia and rhabdomyolysis after 1 dose of bortezomib, and died from a diffuse zygomyces infection on day 17. Five additional patients were enrolled with no subsequent DLTs. As planned, no further dose escalation was pursued. The regimen had predictable toxicity related to the chemotherapy drugs. Two patients had mild peripheral neuropathy (grades 1 and 2). Six of nine evaluable patients (67%) achieved a complete response (CR), and one had a bone marrow CR with persistent central nervous system leukemia.
  
  
  CONCLUSIONS
  The combination of bortezomib (1.3 mg/m(2)) with VXLD is active with acceptable toxicity in pretreated pediatric patients with relapsed ALL. We are expanding the 1.3 mg/m(2) cohort for a phase II estimate of response. Study registered at ClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT00440726).
authors.affiliation: Pediatric Hematology and Oncology, Children's Hospitals and Clinics of Minnesota, St. Paul, Minnesota 55102, USA. yoav.messinger@childrensmn.org
authors.forename: Yoav
authors.initials: Y
authors.lastname: Messinger
authors.forename: Paul
authors.initials: P
authors.lastname: Gaynon
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Raetz
authors.forename: Raymond
authors.initials: R
authors.lastname: Hutchinson
authors.forename: Steven
authors.initials: S
authors.lastname: Dubois
authors.forename: Julia
authors.initials: J
authors.lastname: Glade-Bender
authors.forename: Richard
authors.initials: R
authors.lastname: Sposto
authors.forename: Jeannette
authors.initials: J
authors.lastname: van der Giessen
authors.forename: Elena
authors.initials: E
authors.lastname: Eckroth
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Bostrom
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D001215:Asparaginase; D001897:Boronic Acids / Q000008:administration & dosage* / Q000633:toxicity; D000069286:Bortezomib; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000188:drug therapy*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D011719:Pyrazines / Q000008:administration & dosage* / Q000633:toxicity; D016879:Salvage Therapy; D016896:Treatment Outcome; D014750:Vincristine
chemical_list: D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D014750:Vincristine; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin; D001215:Asparaginase