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
Identifieur interne : 006B78 ( Main/Exploration ); précédent : 006B77; suivant : 006B79Dose 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
Auteurs : Ruth Ladenstein [Australie, Autriche, Italie, France, Royaume-Uni, Israël, Allemagne] ; Ulrike Pötschger ; Dimitris Siabalis ; Alberto Garaventa ; Christophe Bergeron ; Ian J. Lewis ; Jerry Stein ; Janice Kohler ; Peter J. Shaw ; Wolfgang Holter ; Vito Pistoia ; Jean MichonSource :
- Journal of clinical oncology [ 0732-183X ] ; 2011.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Cellule souche.
English descriptors
- KwdEn :
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 x 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/m2 SC allows its integration in an outpatient setting.
Affiliations:
- Allemagne, Australie, Autriche, France, Israël, Italie, Royaume-Uni
- Auvergne-Rhône-Alpes, Bavière, District de Moyenne-Franconie, Nouvelle-Galles du Sud, Rhône-Alpes, Vienne (Autriche), Île-de-France
- Erlangen, Lyon, Paris, Sydney, Vienne (Autriche)
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Shaw</name></author><author><name sortKey="Holter, Wolfgang" sort="Holter, Wolfgang" uniqKey="Holter W" first="Wolfgang" last="Holter">Wolfgang Holter</name></author><author><name sortKey="Pistoia, Vito" sort="Pistoia, Vito" uniqKey="Pistoia V" first="Vito" last="Pistoia">Vito Pistoia</name></author><author><name sortKey="Michon, Jean" sort="Michon, Jean" uniqKey="Michon J" first="Jean" last="Michon">Jean Michon</name></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">11-0116909</idno><date when="2011">2011</date><idno type="stanalyst">PASCAL 11-0116909 INIST</idno><idno type="RBID">Pascal:11-0116909</idno><idno type="wicri:Area/PascalFrancis/Corpus">001F88</idno><idno type="wicri:Area/PascalFrancis/Curation">003F46</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">001B75</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">001B75</idno><idno type="wicri:doubleKey">0732-183X:2011:Ladenstein 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Institute</s1><s2>Vienna</s2><s3>AUT</s3></inist:fA14><country>Autriche</country><placeName><settlement type="city">Vienne (Autriche)</settlement><region nuts="2" type="province">Vienne (Autriche)</region></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Giannina Gaslini Children's Hospital</s1><s2>Genoa</s2><s3>ITA</s3></inist:fA14><country>Italie</country><wicri:noRegion>Giannina Gaslini Children's Hospital</wicri:noRegion></affiliation><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Centre Léon Bérard, Service de Pediatrie</s1><s2>Lyon</s2><s3>FRA</s3></inist:fA14><country>France</country><placeName><region type="region">Auvergne-Rhône-Alpes</region><region type="old region">Rhône-Alpes</region><settlement type="city">Lyon</settlement></placeName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>Institut Curie, Service de Pediatrie</s1><s2>Paris</s2><s3>FRA</s3></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Yorkshire Regional Centre for Pediatric Oncology</s1><s2>Leeds, West Yorkshire</s2><s3>GBR</s3></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Yorkshire Regional Centre for Pediatric Oncology</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Southampton General Hospital</s1><s2>Southampton</s2><s3>GBR</s3></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Southampton General Hospital</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Schneider Children's Medical Centre of Israel</s1><s2>Petah-Tikva</s2><s3>ISR</s3></inist:fA14><country>Israël</country><wicri:noRegion>Schneider Children's Medical Centre of Israel</wicri:noRegion></affiliation><affiliation wicri:level="3"><inist:fA14 i1="09"><s1>The Children's Hospital at Westmead</s1><s2>Sydney</s2><s3>AUS</s3></inist:fA14><country>Australie</country><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="10"><s1>University Children's Hospital</s1><s2>Erlangen</s2><s3>DEU</s3></inist:fA14><country>Allemagne</country><placeName><settlement type="city">Erlangen</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Moyenne-Franconie</region></placeName></affiliation></author><author><name sortKey="Potschger, Ulrike" sort="Potschger, Ulrike" uniqKey="Potschger U" first="Ulrike" last="Pötschger">Ulrike Pötschger</name></author><author><name sortKey="Siabalis, Dimitris" sort="Siabalis, Dimitris" uniqKey="Siabalis D" first="Dimitris" last="Siabalis">Dimitris Siabalis</name></author><author><name sortKey="Garaventa, Alberto" sort="Garaventa, Alberto" uniqKey="Garaventa A" first="Alberto" last="Garaventa">Alberto Garaventa</name></author><author><name sortKey="Bergeron, Christophe" sort="Bergeron, Christophe" uniqKey="Bergeron C" first="Christophe" last="Bergeron">Christophe Bergeron</name></author><author><name sortKey="Lewis, Ian J" sort="Lewis, Ian J" uniqKey="Lewis I" first="Ian J." last="Lewis">Ian J. Lewis</name></author><author><name sortKey="Stein, Jerry" sort="Stein, Jerry" uniqKey="Stein J" first="Jerry" last="Stein">Jerry Stein</name></author><author><name sortKey="Kohler, Janice" sort="Kohler, Janice" uniqKey="Kohler J" first="Janice" last="Kohler">Janice Kohler</name></author><author><name sortKey="Shaw, Peter J" sort="Shaw, Peter J" uniqKey="Shaw P" first="Peter J." last="Shaw">Peter J. Shaw</name></author><author><name sortKey="Holter, Wolfgang" sort="Holter, Wolfgang" uniqKey="Holter W" first="Wolfgang" last="Holter">Wolfgang Holter</name></author><author><name sortKey="Pistoia, Vito" sort="Pistoia, Vito" uniqKey="Pistoia V" first="Vito" last="Pistoia">Vito Pistoia</name></author><author><name sortKey="Michon, Jean" sort="Michon, Jean" uniqKey="Michon J" first="Jean" last="Michon">Jean Michon</name></author></analytic><series><title level="j" type="main">Journal of clinical oncology</title><title level="j" type="abbreviated">J. clin. oncol.</title><idno type="ISSN">0732-183X</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Journal of clinical oncology</title><title level="j" type="abbreviated">J. clin. oncol.</title><idno type="ISSN">0732-183X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Ambulatory</term><term>Autograft</term><term>Cancerology</term><term>Clinical stage</term><term>Dose</term><term>Hematopoietic cell</term><term>Interleukin 2</term><term>Natural killer cell</term><term>Neuroblastoma</term><term>Recombinant protein</term><term>Stem cell</term><term>Subcutaneous</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Interleukine 2</term><term>Dose</term><term>Souscutané</term><term>Neuroblastome</term><term>Protéine recombinante</term><term>Cellule NK</term><term>Autogreffe</term><term>Ambulatoire</term><term>Stade clinique</term><term>Cellule hématopoïétique</term><term>Cellule souche</term><term>Cancérologie</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Cellule souche</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 x 10<sup>6</sup> U rIL-2/m<sup>2</sup> 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<sup>6</sup> U/m<sup>2</sup> SC allows its integration in an outpatient setting.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>Autriche</li><li>France</li><li>Israël</li><li>Italie</li><li>Royaume-Uni</li></country><region><li>Auvergne-Rhône-Alpes</li><li>Bavière</li><li>District de Moyenne-Franconie</li><li>Nouvelle-Galles du Sud</li><li>Rhône-Alpes</li><li>Vienne (Autriche)</li><li>Île-de-France</li></region><settlement><li>Erlangen</li><li>Lyon</li><li>Paris</li><li>Sydney</li><li>Vienne (Autriche)</li></settlement></list><tree><noCountry><name sortKey="Bergeron, Christophe" sort="Bergeron, Christophe" uniqKey="Bergeron C" first="Christophe" last="Bergeron">Christophe Bergeron</name><name sortKey="Garaventa, Alberto" sort="Garaventa, Alberto" uniqKey="Garaventa A" first="Alberto" last="Garaventa">Alberto Garaventa</name><name sortKey="Holter, Wolfgang" sort="Holter, Wolfgang" uniqKey="Holter W" first="Wolfgang" last="Holter">Wolfgang Holter</name><name sortKey="Kohler, Janice" sort="Kohler, Janice" uniqKey="Kohler J" first="Janice" last="Kohler">Janice Kohler</name><name sortKey="Lewis, Ian J" sort="Lewis, Ian J" uniqKey="Lewis I" first="Ian J." last="Lewis">Ian J. Lewis</name><name sortKey="Michon, Jean" sort="Michon, Jean" uniqKey="Michon J" first="Jean" last="Michon">Jean Michon</name><name sortKey="Pistoia, Vito" sort="Pistoia, Vito" uniqKey="Pistoia V" first="Vito" last="Pistoia">Vito Pistoia</name><name sortKey="Potschger, Ulrike" sort="Potschger, Ulrike" uniqKey="Potschger U" first="Ulrike" last="Pötschger">Ulrike Pötschger</name><name sortKey="Shaw, Peter J" sort="Shaw, Peter J" uniqKey="Shaw P" first="Peter J." last="Shaw">Peter J. Shaw</name><name sortKey="Siabalis, Dimitris" sort="Siabalis, Dimitris" uniqKey="Siabalis D" first="Dimitris" last="Siabalis">Dimitris Siabalis</name><name sortKey="Stein, Jerry" sort="Stein, Jerry" uniqKey="Stein J" first="Jerry" last="Stein">Jerry Stein</name></noCountry><country name="Australie"><noRegion><name sortKey="Ladenstein, Ruth" sort="Ladenstein, Ruth" uniqKey="Ladenstein R" first="Ruth" last="Ladenstein">Ruth Ladenstein</name></noRegion><name sortKey="Ladenstein, Ruth" sort="Ladenstein, Ruth" uniqKey="Ladenstein R" first="Ruth" last="Ladenstein">Ruth Ladenstein</name></country><country name="Autriche"><region name="Vienne (Autriche)"><name sortKey="Ladenstein, Ruth" sort="Ladenstein, Ruth" uniqKey="Ladenstein R" first="Ruth" last="Ladenstein">Ruth Ladenstein</name></region></country><country name="Italie"><noRegion><name sortKey="Ladenstein, Ruth" sort="Ladenstein, Ruth" uniqKey="Ladenstein R" first="Ruth" last="Ladenstein">Ruth Ladenstein</name></noRegion></country><country name="France"><region name="Auvergne-Rhône-Alpes"><name sortKey="Ladenstein, Ruth" sort="Ladenstein, Ruth" uniqKey="Ladenstein R" first="Ruth" last="Ladenstein">Ruth Ladenstein</name></region><name sortKey="Ladenstein, Ruth" sort="Ladenstein, Ruth" uniqKey="Ladenstein R" first="Ruth" last="Ladenstein">Ruth Ladenstein</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Ladenstein, Ruth" sort="Ladenstein, Ruth" uniqKey="Ladenstein R" first="Ruth" last="Ladenstein">Ruth Ladenstein</name></noRegion><name sortKey="Ladenstein, Ruth" sort="Ladenstein, Ruth" uniqKey="Ladenstein R" first="Ruth" last="Ladenstein">Ruth Ladenstein</name></country><country name="Israël"><noRegion><name sortKey="Ladenstein, Ruth" sort="Ladenstein, Ruth" uniqKey="Ladenstein R" first="Ruth" last="Ladenstein">Ruth Ladenstein</name></noRegion></country><country name="Allemagne"><region name="Bavière"><name sortKey="Ladenstein, Ruth" sort="Ladenstein, Ruth" uniqKey="Ladenstein R" first="Ruth" last="Ladenstein">Ruth Ladenstein</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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