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.

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.
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.
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.
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.
AuthorsRuth Ladenstein, Ulrike Pötschger, Dimitris Siabalis, Alberto Garaventa, Christophe Bergeron, Ian J Lewis, Jerry Stein, Janice Kohler, Peter J Shaw, Wolfgang Holter, Vito Pistoia, Jean Michon
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 29 Issue 4 Pg. 441-8 (Feb 1 2011) ISSN: 1527-7755 [Electronic] United States
PMID21149662 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial)
Chemical References
  • Antineoplastic Agents
  • Interleukin-2
  • Recombinant Proteins
  • aldesleukin
  • Ambulatory Care
  • Antineoplastic Agents (administration & dosage, adverse effects)
  • Australia
  • Chemotherapy, Adjuvant
  • Child
  • Child, Preschool
  • Disease-Free Survival
  • Dose-Response Relationship, Drug
  • Europe
  • Female
  • Humans
  • Injections, Subcutaneous
  • Interleukin-2 (administration & dosage, adverse effects, analogs & derivatives)
  • Israel
  • Kaplan-Meier Estimate
  • Killer Cells, Natural (drug effects, immunology)
  • Male
  • Neoplasm Staging
  • Neuroblastoma (drug therapy, immunology, mortality, surgery)
  • Recombinant Proteins (administration & dosage, adverse effects)
  • Stem Cell Transplantation
  • Time Factors
  • Transplantation, Autologous
  • Treatment Outcome

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