title: Dose finding study for the use of subcutaneous recombinant interleukin-2 to augment natural killer cell numbers in an outpatient setting for stage 4 neuroblastoma after megatherapy and autologous stem-cell reinfusion.
abstract: OBJECTIVE
  To establish a safe dose of subcutaneous (SC) recombinant interleukin 2 (rIL-2) in an outpatient setting for children with stage 4 neuroblastoma after megatherapy (MGT) and autologous stem-cell reinfusion (ASCR) that is able to sustain an increase of natural-killer cells (NKCs) above the level previously reported for immunomodulatory potency.
  
  
  METHODS
  Between August 1997 and November 2000, 33 patients with stage 4 neuroblastoma entered the study from six countries after receiving MGT/ASCR according to national protocols. Dose levels of 3, 6, and 9 × 10(6) U rIL-2/m(2) were given SC in six 5-day cycles every 2 weeks.
  
  
  RESULTS
  Median age at registration was 4.1 years (range, 1.8 to 7.4). Median observation time was 5 years (range, 4 to 9.8). Increase of NKCs was achieved in 89% of courses, with more than 100% increase over baseline and/or more than 1,000 NKCs/μL in 58%. On the basis of outpatient dose-limiting toxicity at dose level 3, dose level 2 was chosen for the confirmation stage. At dose level 2, the median increase in absolute NKCs was 1,180 cells/μL for all 83 cycles, corresponding to a median relative NKC increase over baseline of 711%. Fever was frequent but controllable with adequate supportive care; 6.5% of patients were hospitalized. Localized pain was moderate and acceptable. Event-free and overall survival rates at 5 years were 45% (± 9 standard deviation [SD]) and 48% (± 9 SD), respectively.
  
  
  CONCLUSIONS
  The low toxicity profile and ability to sustain an increase in NKCs of IL-2 at 6 × 10(6) U/m(2) SC allows its integration in an outpatient setting.
authors.affiliation: St Anna Children's Hospital, Vienna, Austria. ruth.ladenstein@ccri.at
authors.forename: Ruth
authors.initials: R
authors.lastname: Ladenstein
authors.forename: Ulrike
authors.initials: U
authors.lastname: Pötschger
authors.forename: Dimitris
authors.initials: D
authors.lastname: Siabalis
authors.forename: Alberto
authors.initials: A
authors.lastname: Garaventa
authors.forename: Christophe
authors.initials: C
authors.lastname: Bergeron
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Lewis
authors.forename: Jerry
authors.initials: J
authors.lastname: Stein
authors.forename: Janice
authors.initials: J
authors.lastname: Kohler
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Shaw
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Holter
authors.forename: Vito
authors.initials: V
authors.lastname: Pistoia
authors.forename: Jean
authors.initials: J
authors.lastname: Michon
mesh_terms: D000553:Ambulatory Care; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001315:Australia; D017024:Chemotherapy, Adjuvant; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005060:Europe; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D007557:Israel; D053208:Kaplan-Meier Estimate; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008297:Male; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000601:surgery*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D033581:Stem Cell Transplantation; D013997:Time Factors; D014182:Transplantation, Autologous; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007376:Interleukin-2; D011994:Recombinant Proteins; C082598:aldesleukin