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

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

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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 × 106 U rIL-2/m2 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 × 106 U/m 2 SC allows its integration in an outpatient setting.

Original languageEnglish
Pages (from-to)441-448
Number of pages8
JournalJournal of Clinical Oncology
Volume29
Issue number4
DOIs
Publication statusPublished - Feb 1 2011

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Neuroblastoma
Natural Killer Cells
Interleukin-2
Outpatients
Stem Cells
Cell Count
Aptitude
Disease-Free Survival
Fever
Survival Rate
Observation
Pain

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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. / Ladenstein, Ruth; Pötschger, Ulrike; Siabalis, Dimitris; Garaventa, Alberto; Bergeron, Christophe; Lewis, Ian J.; Stein, Jerry; Kohler, Janice; Shaw, Peter J.; Holter, Wolfgang; Pistoia, Vito; Michon, Jean.

In: Journal of Clinical Oncology, Vol. 29, No. 4, 01.02.2011, p. 441-448.

Research output: Contribution to journalArticle

Ladenstein, Ruth ; Pötschger, Ulrike ; Siabalis, Dimitris ; Garaventa, Alberto ; Bergeron, Christophe ; Lewis, Ian J. ; Stein, Jerry ; Kohler, Janice ; Shaw, Peter J. ; Holter, Wolfgang ; Pistoia, Vito ; Michon, Jean. / 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. In: Journal of Clinical Oncology. 2011 ; Vol. 29, No. 4. pp. 441-448.
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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 × 106 U rIL-2/m2 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 × 106 U/m 2 SC allows its integration in an outpatient setting.",
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AU - Ladenstein, Ruth

AU - Pötschger, Ulrike

AU - Siabalis, Dimitris

AU - Garaventa, Alberto

AU - Bergeron, Christophe

AU - Lewis, Ian J.

AU - Stein, Jerry

AU - Kohler, Janice

AU - Shaw, Peter J.

AU - Holter, Wolfgang

AU - Pistoia, Vito

AU - Michon, Jean

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N2 - 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 × 106 U rIL-2/m2 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 × 106 U/m 2 SC allows its integration in an outpatient setting.

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