{Author 1 (Prefix):11.2} {Author 1 (Last):11.6}

TitelAnti-GD2 antibody dinutuximab beta and low-dose subcutaneous IL2 after haploidentical stem cell transplantation in paediatric patients with relapsed neuroblastoma: A multicentre, open label, phase I/II trial
Einleitung

Patients with relapsed neuroblastoma (rHR-NB) have a poor prognosis. We hypothesized that graft-versus-neuroblastoma effects could be elicited by transplantation of haploidentical stem cells (haplo-SCT) exploiting the cytotoxic function of NK-cells and their activation by the anti-GD2 antibody Dinutuximab-beta (DB). This international, multicentre phase I/II-trial assessed safety, feasibility and outcomes of immunotherapy with DB plus subcutaneous interleukin-2 (scIL2) after haplo-SCT in relapsed high-risk neuroblastoma patients.

Patient/en und Methoden

Patients aged 1–21 years underwent haplo-SCT with T-/B-cell-depleted grafts followed by Dinutuximab-beta, 20 mg/m²/day x 5 days for 6 cycles (cycles 4–6 plus 1x106 IU/m² scIL2 x 3 days). Primary endpoint ’success of treatment’ encompassed patients receiving six cycles, being alive 180 days after therapy without progressive disease (PD), unacceptable toxicity, acute graft-versus-host-disease (aGvHD) ≥grade 3 or extensive chronic GvHD.

Ergebnisse

Between November 11, 2010, and November 26, 2017, 70 patients were enrolled, 68 eligible to undergo immunotherapy. Median number of DB-cycles was six (range 1-9, 4.1% dose reductions; 23% stopping early). Median number of scIL2-cycles was 3 (range 1-6, 1.6% stopping early). Primary endpoint was met by 37 patients (54,4 %). Median observation time was 7.8 years. Five-year event-free (EFS) and overall survival (OS) were 43% [95% CI31-55] and 53% [41-65]. Five-year EFS among patients in complete remission (CR) (52% [31-69]) or partial remission (44% [27-60]) prior immunotherapy were significantly better compared with patients with mixed/non-response/PD (13% [1-42], p=0,026). Overall response rate in 43 patients with evidence of disease after haplo-SCT, was 51% (22 patients), with 15 achieving CR (35%). Two patients developed GvHD grade 2/3 during treatment; no unexpected adverse events occurred.

Schlussfolgerung/Diskussion

DB-therapy after haplo-SCT is feasible with low risk of inducing GvHD and results in improved long-term remissions likely attributable to increased anti-tumour activity by donor-derived effector cells.

Autor*in 1Ruth Ladenstein St Anna Children’s Hospital and Children’s Cancer Research Institute, Department of Studies and Statistics for Integrated Research and Projects; Department of Paediatrics, Medical University of Vienna, Vienna, Austria
Autor*in 2Tim Flaadt Department of Hematology and Oncology, University Children’s Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany
Autor*in 3Martin Ebinger Department of Hematology and Oncology, University Children’s Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany
Autor*in 4Holger N. Lode Department of Pediatric Hematology and Oncology, University Medicine Greifswald, Greifswald, Germany
Autor*in 5Helga Björk Arnardóttir Department for Studies and Statistics and Integrated Research, Children's Cancer Research Institute, Vienna, Austria.
Autor*in 6Ulrike Poetschger Department for Studies and Statistics and Integrated Research, Children's Cancer Research Institute, Vienna, Austria.
Autor*in 7Wolfgang Schwinger Division of Pediatric Hematology-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University Graz, Graz, Austria.
Autor*in 8Roland Meisel Division of Pediatric Stem Cell Therapy, Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
Autor*in 9Friedhelm R. Schuster Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany
Autor*in 10Michaela Döring Department of Hematology and Oncology, University Children’s Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany
Autor*in 11Peter F. Ambros St Anna Children’s Hospital and Children’s Cancer Research Institute, Department of Studies and Statistics for Integrated Research and Projects; Department of Paediatrics, Medical University of Vienna, Vienna, Austria
Autor*in 12Ursula Holzer Department of Hematology and Oncology, University Children’s Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany
Autor*in 13Tobias Feuchtinger Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Dr. von Hauner Children's Hospital, University Hospital, Ludwig Maximilians University Munich, Munich, Germany
Autor*in 14Thorston Simon Department of Pediatric Oncology and Hematology, University Hospital, University of Cologne
Autor*in 15Johannes Schulte Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin
Autor*in 16Angelika Eggert Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany
Autor*in 17Heiko-Manuel Teltschik Department of Hematology and Oncology, Children's Hospital Stuttgart - Olgahospital, Stuttgart, Germany
Autor*in 18Toni Illhardt Department of Hematology and Oncology, University Children’s Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany
Autor*in 19Rupert Handgretinger Department of Hematology and Oncology, University Children’s Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany
Autor*in 20Peter Lang Department of Hematology and Oncology, University Children’s Hospital, Eberhard Karls University Tuebingen, Tuebingen, Germany