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

PURPOSE:

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.

PATIENTS AND 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.

CONCLUSION:

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: Ruth 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
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 29 Issue 4 Pg. 441-8 (Feb 01 2011) ISSN: 1527-7755 [Electronic] United States
• PMID: 21149662 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Antineoplastic Agents
• Interleukin-2
• Recombinant Proteins
• aldesleukin

Topics

• 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