High-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma (SIOPEN)
- Conditions
- Interventions
- Registration Number
- NCT04221035
- Lead Sponsor
- Gustave Roussy, Cancer Campus, Grand Paris
- Brief Summary
This is an international multicenter, open-label, randomized phase III trial including three sequential randomizations to assess efficacy of induction and consolidation chemotherapies and radiotherapy for patients with high-risk neuroblastoma.
- Detailed Description
This is an international multicenter, open-label, randomized phase III trial including three sequential randomizations to assess efficacy of induction and consolidation chemotherapies and radiotherapy for patients with high-risk neuroblastoma.
...
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 800
Enrollment in HR-NBL2 will be performed:
- at diagnosis before the beginning of chemotherapy or
- up to 21 days after one course of Carboplatin-Etoposide for patients with localized neuroblastoma or infants with metastatic neuroblastoma with MYCN amplification or patients with metastatic neuroblastoma treated in emergency or
- up to 21 days after one course of the current protocol for R-I randomisation (RAPID COJEC/GPOH) low/intermediate risk neuroblastoma in Germany/Netherlands for patients with localized neuroblastoma or infants with metastatic neuroblastoma with MYCN amplification
HR-NBL2 eligibility criteria:
-
Established diagnosis of neuroblastoma according to the SIOPEN- modified International Neuroblastoma Risk Group (INRG) criteria, High-risk neuroblastoma defined as:
- Stage M neuroblastoma above 365 days of age at diagnosis (no upper age limit) and Ms neuroblastoma 12-18 months old, any MYCN status or
- L2, M or Ms neuroblastoma any age with MYCN amplification, or focal high level MYC or MYCL amplification.
In Germany, patients aged less than 18 months with stage M and without MYCN amplification will not be enrolled in HR-NBL2 trial.
-
No previous chemotherapy or up to 21 days after one cycle of Carboplatin-Etoposide chemotherapy for patients with localized neuroblastoma or infants with metastatic neuroblastoma with MYCN amplification or patients with metastatic neuroblastoma treated in emergency or up to 21 days after one course of the current protocol for low/intermediate risk neuroblastoma in Germany/Netherlands for patients with localized neuroblastoma or infants with metastatic neuroblastoma with MYCN amplification
-
Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to initiation of treatment. Sexually active patients must agree to use acceptable and appropriate contraception while on HR-NBL2 study and for one year after stopping the study. Acceptable contraception is defined in CTFG Guidelines "Recommendations related to contraception and pregnancy testing in clinical trials" (Appendix 11). Female patients who are lactating must agree to stop breast-feeding.
-
Written informed consent to enter the HR-NBL2 protocol from patient or parents/legal representative, patient, and age-appropriate assent.
-
Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
-
Patients should be able and willing to comply with study visits and procedures as per protocol
R-I eligibility criteria:
- Written informed consent to enter the R-I randomisation from patient or parents/legal representative, patient, and age- appropriate assent.
In case of parents'/patient's refusal to R-I, or Organ toxicity exclusion criteria at diagnosis, patients can still be enrolled in HR- NBL2 trial with parents'/patient's consent before or within 3 weeks from the beginning of chemotherapy
R-HDC randomisation (Single HDC Bu-Mel/ Tandem HDC Thiotepa+Bu-Mel) Etoposide or one course of the current protocol for low/intermediate risk neuroblastoma in Germany/Netherlands). Patients will be treated with the standard induction regimen per country (Rapid COJEC or GPOH) and will be potentially eligible for subsequent randomisations.
Randomisation for HDC strategy will be performed at the end of induction after the disease evaluation and after surgery of the primary tumour for those patients who will receive surgery before HDC.
R-HDC eligibility criteria:
-
- Stage M neuroblastoma above 365 days of age at diagnosis, any MYCN status, EXCEPT patients with stage M or Ms 12-18 months old with numerical chromosomal alterations only, and in complete metastatic response at the end of induction: in this case, patients will have surgery and no further treatment.
OR
- L2, M or Ms neuroblastoma, any age, with MYCN amplification, or focal high level MYC or MYCL amplification
-
Age < 21 years at the time of randomization
-
Complete response (CR) or partial response (PR) at metastatic sites:
- Bone disease: mIBG uptake completely resolved or SIOPEN score ≤ 3 and at least 50% reduction in mIBG score (or ≤ 3 bone lesions and at least 50% reduction in number of FDG- PET-avid bone lesions for mIBG-nonavid tumours).
- Bone marrow disease: CR and/or minimal disease (MD) according to International Neuroblastoma Response Criteria
- Other metastatic sites: CR. (after induction chemotherapy +/- surgery), except for distant lymph nodes for which PR is accepted with a possible secondary surgery
-
Acceptable organ function and performance status:
- Performance status ≥ 50%.
- Hematological status: ANC>0.5x109/L, platelets > 20x 109/L
- Cardiac function: (< grade 2)
- Normal chest X-Ray and oxygen saturation.
- Absence of any toxicity ≥ grade 3. 4) Sufficient collected stem cells available; a total harvest of at least 6 x 106/kg CD34+ cells, to be stored in at least 4 separate bags to administer at least 3 x 106/kg CD34+ cells per rescue.
-
Written informed consent, including agreement of patient or parents/legal guardian for minors, to enter the R-HDC randomisation.
-
Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
-
Patients should be able and willing to comply with study visits and procedures as per protocol.
In case of parents'/patient's refusal, or insufficient stem cells, collection for tandem HDC but with a minimum of 3 x 106 CD34+ cells/kg body weight, or in case of patients older than 21 years, or organ toxicity, HDC will consist on the standard HD Bu-Mel and patients will be eligible for the subsequent randomisation.
R-RTx randomisation (Local Radiotherapy) Chemoimmunotherapy arm
R-RTx eligibility criteria:
An evaluation of the local disease will be performed after HDC/ASCR and surgery:
-
In case of no local macroscopic disease, all patients will receive 21,6-Gy radiotherapy to the pre-operative tumour bed
-
In case of local macroscopic residual disease, patients will be eligible to R-RTx if the following criteria are met:
- No evidence of disease progression after HDC/ASCR.
- Interval between the last ASCR and radiotherapy start between 60 and 90 days.
- Performance status greater or equal 50%.
- Hematological status: ANC >0.5x109/L, platelets > 20x109/L.
- Written informed consent, including agreement of patient or parents/legal guardian for minors, to enter the R-RTx randomisation.
- Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
- Patients should be able and willing to comply with study visits and procedures as per protocol.
In case of parents'/patient's refusal of the randomisation, the patient will receive 21.6 Gy radiotherapy to the pre-operative tumour bed.
Chemoimmunotherapy arm eligibility criteria:
-
Insufficient metastatic response at the end of induction chemotherapy, defined as:
- SIOPEN score > 3 or less than 50% reduction in mIBG score (or > 3 bone lesions or less 50% reduction in number of FDG-PET-avid bone lesions for mIBG-non avid tumours) OR
- Bone marrow disease: SD according to International Neuroblastoma Response Criteria OR
- Other metastatic sites: PR or SD. For distant lymph nodes: PR and not resectable or SD.
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Performance status ≥ 50%.
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Hematological status: ANC>0.75x109/L without G-CSF for at least 48 hours (or ANC ≥ 0.50 x 109 /L in case of bone marrow involvement), platelets > 50x 109/L and rising, without platelets transfusion for 72 hours.
-
AST or ALT ≤7.5 ULN and total bilirubin ≤1.5 ULN. In patients with liver metastases, total bilirubin ≤2.5 ULN is allowed.
-
No active infection;
-
No grade >2 gastrointestinal toxicity.
-
No grade ≥ 3 toxicity related to previous treatment.
-
Oxygen saturation > 94%
Non-inclusion criteria for HR-NBL2:
- Any negative answer concerning the HR-NLB2 inclusion criteria
- Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving his consent.
- Participating in another clinical study with an IMP while on study treatment.
- Chronic inflammatory bowel disease and/or bowel obstruction.
- Pregnant or breastfeeding women.
- Known hypersensitivity to the active substance or to any of the excipients of the study drugs
- Concomitant self-medication medicine that in the investigator opinion could interact with study treatments, including herbal medicine (e.g. St John's Wort (Hypericum Perforatum).
Non-inclusion criteria specific to the R-I randomisation (RAPID COJEC/GPOH):
- Urinary tract obstruction ≥ grade 3
- Heart failure or myocarditis ≥ grade 2, any arrhythmia or myocardial infection
- Peripheral motor or sensory neuropathy ≥ grade 3
- Demyelinating form of Charcot-Marie-Tooth syndrome
- Hearing impairment ≥ grade 2
- Concurrent prophylactic use of phenytoin
- Cardiorespiratory disease that contraindicates hyperhydration
Non-inclusion criteria common to all randomisations (R-I, R-HDC, and R-RTx):
- Any negative answer concerning the inclusion criteria of R-I or R- HDC or R-RTx will render the patient ineligible for the corresponding therapy phase randomisation. However, these patients may remain on study and be considered to receive standard treatment of the respective therapy phase, and may be potentially eligible for subsequent randomisations.
- Liver function: Alanine aminotransferase (ALT) > 3.0 x ULN and blood bilirubin > 1.5 x ULN (toxicity ≥ grade 2). In case of toxicity ≥ grade 2, call national principal investigator study coordinator to discuss the feasibility.
- Renal function: Creatinine clearance and/or GFR < 60 ml/min/1.73m² (toxicity ≥ grade 2). If GFR < 60ml/min/1.73m², call national principal investigator study coordinator to discuss about the treatment.
- Dyspnea at rest and/or pulse oximetry <95% in air (only for R-HDC, and R-RTx)
- Any uncontrolled intercurrent illness or infection that in the investigator opinion would impair study participation.
- Concomitant use with yellow fever vaccine and with live virus or bacterial vaccines.
- Patient allergic to peanut or soya.
Non-inclusion criteria to R-HDC:
- Any negative answer concerning the R-HDC inclusion criteria
Non-inclusion criteria to chemoimmunotherapy arm:
- Any negative answer concerning the inclusion criteria of chemoimmunotherapy arm.
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description phase induction-R-I Etoposide R-I: induction regimens RAPID COJEC vs GPOH Assuming a baseline 3-year EFS of 40%, with a sample size of 686 patients (343 in each arm) and a two-sided alpha=5% this trial will have 90% power to demonstrate an improvement of 12% in 3-year EFS, within a recruitment period of 3 years and a minimum follow up of 1.5 years. Patients with insufficient metastatic response at the end of induction chemotherapy, defined as SIOPEN score \> 3 or less than 50% reduction in mIBG score (or \> 3 bone lesions or less 50% reduction in number of FDG-PET-avid bone lesions for mIBG-non avid tumours), have a poorer prognosis. Chemoimmunotherapy arm Metastatic response rate after 4 courses of irinotecan-temozolomide (TEMIRI) combined with dinutuximab beta (DB) in patients with insufficient metastatic response at the end of induction chemotherapy (TEMIRI/DB). Phase of radiotherapy Radiotherapy R-RTx: 21.6 Gy radiotherapy vs 21.6 Gy + 14.4 Gy boost in patients with macroscopic residual disease phase induction-R-I Temozolomide 100 MG R-I: induction regimens RAPID COJEC vs GPOH Assuming a baseline 3-year EFS of 40%, with a sample size of 686 patients (343 in each arm) and a two-sided alpha=5% this trial will have 90% power to demonstrate an improvement of 12% in 3-year EFS, within a recruitment period of 3 years and a minimum follow up of 1.5 years. Patients with insufficient metastatic response at the end of induction chemotherapy, defined as SIOPEN score \> 3 or less than 50% reduction in mIBG score (or \> 3 bone lesions or less 50% reduction in number of FDG-PET-avid bone lesions for mIBG-non avid tumours), have a poorer prognosis. Chemoimmunotherapy arm Metastatic response rate after 4 courses of irinotecan-temozolomide (TEMIRI) combined with dinutuximab beta (DB) in patients with insufficient metastatic response at the end of induction chemotherapy (TEMIRI/DB). Phase of radiotherapy Dinutuximab Beta R-RTx: 21.6 Gy radiotherapy vs 21.6 Gy + 14.4 Gy boost in patients with macroscopic residual disease phase induction-R-I Vincristine R-I: induction regimens RAPID COJEC vs GPOH Assuming a baseline 3-year EFS of 40%, with a sample size of 686 patients (343 in each arm) and a two-sided alpha=5% this trial will have 90% power to demonstrate an improvement of 12% in 3-year EFS, within a recruitment period of 3 years and a minimum follow up of 1.5 years. Patients with insufficient metastatic response at the end of induction chemotherapy, defined as SIOPEN score \> 3 or less than 50% reduction in mIBG score (or \> 3 bone lesions or less 50% reduction in number of FDG-PET-avid bone lesions for mIBG-non avid tumours), have a poorer prognosis. Chemoimmunotherapy arm Metastatic response rate after 4 courses of irinotecan-temozolomide (TEMIRI) combined with dinutuximab beta (DB) in patients with insufficient metastatic response at the end of induction chemotherapy (TEMIRI/DB). phase induction-R-I Carboplatin R-I: induction regimens RAPID COJEC vs GPOH Assuming a baseline 3-year EFS of 40%, with a sample size of 686 patients (343 in each arm) and a two-sided alpha=5% this trial will have 90% power to demonstrate an improvement of 12% in 3-year EFS, within a recruitment period of 3 years and a minimum follow up of 1.5 years. Patients with insufficient metastatic response at the end of induction chemotherapy, defined as SIOPEN score \> 3 or less than 50% reduction in mIBG score (or \> 3 bone lesions or less 50% reduction in number of FDG-PET-avid bone lesions for mIBG-non avid tumours), have a poorer prognosis. Chemoimmunotherapy arm Metastatic response rate after 4 courses of irinotecan-temozolomide (TEMIRI) combined with dinutuximab beta (DB) in patients with insufficient metastatic response at the end of induction chemotherapy (TEMIRI/DB). phase induction-R-I Vindesine R-I: induction regimens RAPID COJEC vs GPOH Assuming a baseline 3-year EFS of 40%, with a sample size of 686 patients (343 in each arm) and a two-sided alpha=5% this trial will have 90% power to demonstrate an improvement of 12% in 3-year EFS, within a recruitment period of 3 years and a minimum follow up of 1.5 years. Patients with insufficient metastatic response at the end of induction chemotherapy, defined as SIOPEN score \> 3 or less than 50% reduction in mIBG score (or \> 3 bone lesions or less 50% reduction in number of FDG-PET-avid bone lesions for mIBG-non avid tumours), have a poorer prognosis. Chemoimmunotherapy arm Metastatic response rate after 4 courses of irinotecan-temozolomide (TEMIRI) combined with dinutuximab beta (DB) in patients with insufficient metastatic response at the end of induction chemotherapy (TEMIRI/DB). phase induction-R-I Dacarbazine R-I: induction regimens RAPID COJEC vs GPOH Assuming a baseline 3-year EFS of 40%, with a sample size of 686 patients (343 in each arm) and a two-sided alpha=5% this trial will have 90% power to demonstrate an improvement of 12% in 3-year EFS, within a recruitment period of 3 years and a minimum follow up of 1.5 years. Patients with insufficient metastatic response at the end of induction chemotherapy, defined as SIOPEN score \> 3 or less than 50% reduction in mIBG score (or \> 3 bone lesions or less 50% reduction in number of FDG-PET-avid bone lesions for mIBG-non avid tumours), have a poorer prognosis. Chemoimmunotherapy arm Metastatic response rate after 4 courses of irinotecan-temozolomide (TEMIRI) combined with dinutuximab beta (DB) in patients with insufficient metastatic response at the end of induction chemotherapy (TEMIRI/DB). phase induction-R-I Ifosfamide R-I: induction regimens RAPID COJEC vs GPOH Assuming a baseline 3-year EFS of 40%, with a sample size of 686 patients (343 in each arm) and a two-sided alpha=5% this trial will have 90% power to demonstrate an improvement of 12% in 3-year EFS, within a recruitment period of 3 years and a minimum follow up of 1.5 years. Patients with insufficient metastatic response at the end of induction chemotherapy, defined as SIOPEN score \> 3 or less than 50% reduction in mIBG score (or \> 3 bone lesions or less 50% reduction in number of FDG-PET-avid bone lesions for mIBG-non avid tumours), have a poorer prognosis. Chemoimmunotherapy arm Metastatic response rate after 4 courses of irinotecan-temozolomide (TEMIRI) combined with dinutuximab beta (DB) in patients with insufficient metastatic response at the end of induction chemotherapy (TEMIRI/DB). phase induction-R-I Dinutuximab Beta R-I: induction regimens RAPID COJEC vs GPOH Assuming a baseline 3-year EFS of 40%, with a sample size of 686 patients (343 in each arm) and a two-sided alpha=5% this trial will have 90% power to demonstrate an improvement of 12% in 3-year EFS, within a recruitment period of 3 years and a minimum follow up of 1.5 years. Patients with insufficient metastatic response at the end of induction chemotherapy, defined as SIOPEN score \> 3 or less than 50% reduction in mIBG score (or \> 3 bone lesions or less 50% reduction in number of FDG-PET-avid bone lesions for mIBG-non avid tumours), have a poorer prognosis. Chemoimmunotherapy arm Metastatic response rate after 4 courses of irinotecan-temozolomide (TEMIRI) combined with dinutuximab beta (DB) in patients with insufficient metastatic response at the end of induction chemotherapy (TEMIRI/DB). phase induction-R-I Irinotecan R-I: induction regimens RAPID COJEC vs GPOH Assuming a baseline 3-year EFS of 40%, with a sample size of 686 patients (343 in each arm) and a two-sided alpha=5% this trial will have 90% power to demonstrate an improvement of 12% in 3-year EFS, within a recruitment period of 3 years and a minimum follow up of 1.5 years. Patients with insufficient metastatic response at the end of induction chemotherapy, defined as SIOPEN score \> 3 or less than 50% reduction in mIBG score (or \> 3 bone lesions or less 50% reduction in number of FDG-PET-avid bone lesions for mIBG-non avid tumours), have a poorer prognosis. Chemoimmunotherapy arm Metastatic response rate after 4 courses of irinotecan-temozolomide (TEMIRI) combined with dinutuximab beta (DB) in patients with insufficient metastatic response at the end of induction chemotherapy (TEMIRI/DB). phase induction-R-I Doxorubicin R-I: induction regimens RAPID COJEC vs GPOH Assuming a baseline 3-year EFS of 40%, with a sample size of 686 patients (343 in each arm) and a two-sided alpha=5% this trial will have 90% power to demonstrate an improvement of 12% in 3-year EFS, within a recruitment period of 3 years and a minimum follow up of 1.5 years. Patients with insufficient metastatic response at the end of induction chemotherapy, defined as SIOPEN score \> 3 or less than 50% reduction in mIBG score (or \> 3 bone lesions or less 50% reduction in number of FDG-PET-avid bone lesions for mIBG-non avid tumours), have a poorer prognosis. Chemoimmunotherapy arm Metastatic response rate after 4 courses of irinotecan-temozolomide (TEMIRI) combined with dinutuximab beta (DB) in patients with insufficient metastatic response at the end of induction chemotherapy (TEMIRI/DB). Phase high dose chemotherapy consolidation Busulfan R-HDC: consolidation regimen Bu-Mel vs Thiotepa + Bu-Mel The 3-year EFS in the Bu-Mel arm (with immunotherapy) is estimated to be 55%. This study aims to show an improvement of 12% for the Thiotepa + Bu-Mel arm (3-year EFS of 67%). With a recruitment of 448 patients (224 in each arm) over a period of 3 years and a minimum follow-up of 2 years, the power to show a 12% difference is 80% (two-sided logrank test and α=5%). phase induction-R-I Cisplatin R-I: induction regimens RAPID COJEC vs GPOH Assuming a baseline 3-year EFS of 40%, with a sample size of 686 patients (343 in each arm) and a two-sided alpha=5% this trial will have 90% power to demonstrate an improvement of 12% in 3-year EFS, within a recruitment period of 3 years and a minimum follow up of 1.5 years. Patients with insufficient metastatic response at the end of induction chemotherapy, defined as SIOPEN score \> 3 or less than 50% reduction in mIBG score (or \> 3 bone lesions or less 50% reduction in number of FDG-PET-avid bone lesions for mIBG-non avid tumours), have a poorer prognosis. Chemoimmunotherapy arm Metastatic response rate after 4 courses of irinotecan-temozolomide (TEMIRI) combined with dinutuximab beta (DB) in patients with insufficient metastatic response at the end of induction chemotherapy (TEMIRI/DB). phase induction-R-I Cyclophosphamid R-I: induction regimens RAPID COJEC vs GPOH Assuming a baseline 3-year EFS of 40%, with a sample size of 686 patients (343 in each arm) and a two-sided alpha=5% this trial will have 90% power to demonstrate an improvement of 12% in 3-year EFS, within a recruitment period of 3 years and a minimum follow up of 1.5 years. Patients with insufficient metastatic response at the end of induction chemotherapy, defined as SIOPEN score \> 3 or less than 50% reduction in mIBG score (or \> 3 bone lesions or less 50% reduction in number of FDG-PET-avid bone lesions for mIBG-non avid tumours), have a poorer prognosis. Chemoimmunotherapy arm Metastatic response rate after 4 courses of irinotecan-temozolomide (TEMIRI) combined with dinutuximab beta (DB) in patients with insufficient metastatic response at the end of induction chemotherapy (TEMIRI/DB). Phase high dose chemotherapy consolidation Melphalan R-HDC: consolidation regimen Bu-Mel vs Thiotepa + Bu-Mel The 3-year EFS in the Bu-Mel arm (with immunotherapy) is estimated to be 55%. This study aims to show an improvement of 12% for the Thiotepa + Bu-Mel arm (3-year EFS of 67%). With a recruitment of 448 patients (224 in each arm) over a period of 3 years and a minimum follow-up of 2 years, the power to show a 12% difference is 80% (two-sided logrank test and α=5%). Phase high dose chemotherapy consolidation Thiotepa R-HDC: consolidation regimen Bu-Mel vs Thiotepa + Bu-Mel The 3-year EFS in the Bu-Mel arm (with immunotherapy) is estimated to be 55%. This study aims to show an improvement of 12% for the Thiotepa + Bu-Mel arm (3-year EFS of 67%). With a recruitment of 448 patients (224 in each arm) over a period of 3 years and a minimum follow-up of 2 years, the power to show a 12% difference is 80% (two-sided logrank test and α=5%).
- Primary Outcome Measures
Name Time Method Event free survival (EFS) Assessed at each end of randomization sequences up to one year Event free survival
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (137)
University General Hospital of Thessaloniki "AHEPA"
🇬🇷Thessaloniki, Greece
Children's General Hospital "AGHIA SOFIA"
🇬🇷Athens, Greece
instituto Giannina Gaslini genova
🇮🇹Genova, Italy
CHRU Nancy-Hôpital Brabois Enfant
🇫🇷Nancy, France
Centre Antoine Lacassagne
🇫🇷Nice, France
Hôpital Américain -CHU Reims
🇫🇷Reims, France
Centre Eugène Marquis
🇫🇷Rennes, France
CHU Tours Hôpital Clocheville
🇫🇷Tours, France
charite universitatsmedizin Berlin
🇩🇪Berlin, Germany
Princess Maxima center
🇳🇱Utrecht, Netherlands
NÚDCH- National Institute of Children's Diseases,
🇸🇰Bratislava, Slovakia
University Hospital Northern Norway, Tromsoe
🇳🇴Tromsø, Norway
St Olavs Hospital,
🇳🇴Trondheim, Norway
Hospital Universitario Son Espases
🇪🇸Balea, Spain
Hospital Regional Universitario de Málaga
🇪🇸Málaga, Spain
Sahlgrenska University Hospital
🇸🇪Gothenburg, Sweden
Linköping University Hospital
🇸🇪Linköping, Sweden
Skåne University Hospital
🇸🇪Lund, Sweden
Norrland University Hospital
🇸🇪Umeå, Sweden
Karolinska University Hospital, Stockholm
🇸🇪Stockholm, Sweden
Uppsala University Hospital
🇸🇪Uppsala, Sweden
Royal Belfast Hospital for Sick Children
🇬🇧Belfast, United Kingdom
Birmingham children's Hospital
🇬🇧Birmingham, United Kingdom
Addenbrookes Hospital, Cambridge
🇬🇧Cambridge, United Kingdom
Royal Hospital for Children Glasgow
🇬🇧Glasgow, United Kingdom
Royal Victoria Infirmary, Newcastle
🇬🇧Newcastle, United Kingdom
Nottingham Children's Hospital
🇬🇧Nottingham, United Kingdom
Sheffield Children's Hospital
🇬🇧Sheffield, United Kingdom
Royal Manchester Children's Hospital
🇬🇧Manchester, United Kingdom
Royal Aberdeen Children's Hospital
🇬🇧Aberdeen, United Kingdom
University Hospitals Birmingham Queen Elisabeth Hospital(UHB)
🇬🇧Birmingham, United Kingdom
University Hospitals Bristol and Weston NHS Foundation Trust
🇬🇧Bristol, United Kingdom
Noah's Ark Children's Hospital for Wales - Cardiff
🇬🇧Cardiff, United Kingdom
Great Ormond Street Hospital - London
🇬🇧London, United Kingdom
Royal Hospital for Sick Children - Edinburgh
🇬🇧Edinburgh, United Kingdom
Leeds General Infirmary
🇬🇧Leeds, United Kingdom
Alder Hey Children's Hospital - Liverpool
🇬🇧Liverpool, United Kingdom
Southampton General Hospital
🇬🇧Southampton, United Kingdom
Royal Marsden Hospital
🇬🇧Sutton, United Kingdom
Hospital Universitario Vall D´Hebron
🇪🇸Barcelona, Spain
Hospital Universitario Infantil Niño Jesús
🇪🇸Madrid, Spain
Hospital Universitario Cruces
🇪🇸Cruces, Spain
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Hospital Universitario Donostia
🇪🇸San Sebastián, Spain
Hospital Universitario Virgen del Rocío
🇪🇸Sevilla, Spain
IUCT Oncopole
🇫🇷Toulouse, France
Children's Cancer Centre, Monash Children's Hospital
🇦🇺Clayton, Australia
Oncology/Haematology Department, Perth Children's Hospital
🇦🇺Nedlands, Australia
Sydney children Hospital
🇦🇺Sydney, Randwick, Australia
Australian and New Zealand Children's Hematology/oncology Group
🇦🇺Sydney, Australia
Children's Cancer & Haematology Services, John Hunter Children's Hospital
🇦🇺New Lambton Heights, Australia
sydney children Hospital
🇦🇺Sydney, Australia
Cancer Centre for Children, The Children's Hospital
🇦🇺Westmead, Australia
Cliniques Universitaires Saint-Luc (UCL)
🇧🇪Brussel, Belgium
University Hospitals Leuven
🇧🇪Leuven, Belgium
CHR Citadelle
🇧🇪Liège, Belgium
University Hospital Motol
🇨🇿Prague,, Prague, Czechia
Klinika dětské onkologie FN Brno
🇨🇿Brno, Czechia
Department of Paediatrics and Adolescent Medicine, Rigshospitalet
🇩🇰Copenhagen, Denmark
Aarhus University Hospital
🇩🇰Aarhus, Denmark
New Children's Hospital, Helsinki University Hospital, Helsinki and Uusimaa Hospital District
🇫🇮Helsinki, Finland
The Hans Christian Andersen Children's Hospital, University of Southern Denmark
🇩🇰Odense, Denmark
Kuopio University Hospital
🇫🇮Kuopio, Finland
Turku University Hospital
🇫🇮Turku, Finland
Hôpital de la Mère et de l'Enfant - CHU Limoges
🇫🇷Limoges, France
Centre Léon Berard
🇫🇷Lyon, France
National Cancer Institute
🇱🇹Vilnius, Lithuania
Oslo University Hospital
🇳🇴Oslo, Norway
Children's University Hospital Banská Bystrica
🇸🇰Banská Bystrica, Slovakia
University medical center Ljubljana, University Children's Hospital Ljubljana, Slovenia
🇸🇮Ljubljana, Slovenia
Hospital Clínico Universitario Virgen de la Arrixaca
🇪🇸El Palmar, Spain
Hospital Universitario Politécnico de La FE
🇪🇸Valence, Spain
Hospital Clínico Universitario de Santiago
🇪🇸Santiago De Compostela, Spain
Inselspital, Universitätsklinik für Kinderheilkunde
🇨🇭Bern, Switzerland
Division of Pediatric Oncology Universitäts-Kinderspital Zürich
🇨🇭Zürich, Switzerland
Luzerner Kantonsspital, Kinderspital pädiatrische Hämatologie/Onkologie
🇨🇭Lucerne, Switzerland
University Hospital Gent
🇧🇪Gent, Belgium
Oulu University Hospital
🇫🇮Oulu, Finland
centre Oscar lambert
🇫🇷Lille, France
Institut de cancérologie de Loraine
🇫🇷Nancy, France
CHU Nice-Hôpital d'Archet
🇫🇷Nice, France
CHU Poitiers
🇫🇷Poitiers, France
CHU Rennes
🇫🇷Rennes, France
Hopital des enfants-CHU Toulouse
🇫🇷Toulouse, France
Hôpital Universitaire des Enfants Reine Fabiola (ULB)
🇧🇪Brussels, Belgium
CHU angers
🇫🇷Angers, France
CHU-Pôle Médico-Chirurgical de l'Enfant et l'Adolescant
🇫🇷Besançon, France
CHU Bordeaux
🇫🇷Bordeaux, France
Centre François Baclesse
🇫🇷Caen, France
CHU Estaing
🇫🇷Clermont-Ferrand, France
Centre Georges-François Leclerc
🇫🇷Dijon, France
hopital la Timone
🇫🇷Marseille, France
CHU Saint Etienne
🇫🇷Saint-Étienne, France
Hôpital Armand Trousseau
🇫🇷Paris, France
CHU Brest
🇫🇷Brest, France
CHU de Caen
🇫🇷Caen, France
Hopital d'enfants Marechal de lattre
🇫🇷Dijon, France
Hôpital Couple-Enfant CHU de Grenoble
🇫🇷Grenoble, France
Chu de La Reunion - St Denis
🇫🇷La Réunion, France
Hôpital des Enfants - CHU Rouen
🇫🇷Rouen, France
Institut de cancérologie de l'Ouest - Sité René Gauducheau
🇫🇷Saint-Herblain, France
CHU Haute Pierre
🇫🇷Strasbourg, France
Institut de Cancérologie Strasbourg
🇫🇷Strasbourg, France
A.O.U Policlinico di Bari
🇮🇹Bari, Italy
IRCCS "Istituto Giannina Gaslini"
🇮🇹Genova, Italy
Azienda Policlinico di Modena
🇮🇹Modena, Italy
Policlino San matteo di Pavia
🇮🇹Pavia, Italy
Tampere University Hospital
🇫🇮Tampere, Finland
Children's General Hospital "I AGHIA SOFIA"
🇬🇷Athens, Greece
Spedali civili Ospedale Dei Bambini Oncoematologia pediatrica e TMO
🇮🇹Brescia, Italy
Azienda ospedaliero universitaria di Parma
🇮🇹Parma, Italy
Haukeland University Hospital
🇳🇴Haukeland, Norway
HUG Hôpitaux Universitaires de Genève Unité d'Hémato-Oncologie Pédiatrique
🇨🇭Geneva, Switzerland
Gustave Roussy
🇫🇷Villejuif, Val De Marne, France
CHU d'AMIENS
🇫🇷Amiens, France
Groupe Hospitalier Pellegrin - Chu - Bordeaux
🇫🇷Bordeaux, France
CHU Brest - Hôpital du Morvan
🇫🇷Brest, France
Uniklinik Köln, Klinik und Poliklinik für Kinder und Jugendmedizin
🇩🇪Köln, Germany
Children's General Hospital "P. & A. KYRIAKOU"
🇬🇷Athens, Greece
General Hospital of Thessaloniki "IPPOKRATIO"
🇬🇷Thessaloniki, Greece
Azienda ospedaliero universtaria Anna Meyer
🇮🇹Firenze, Italy
U.O Pediatria, SS Oncoematologia pediatrica
🇮🇹Rimini, Italy
Vilnius University Hospital Santaros Klinikos
🇱🇹Vilnius, Lithuania
institut Curie
🇫🇷Paris, France
"MITERA" Private, General, Obstetrics - Gynaecology, Paediatric Clinic S.A.
🇬🇷Athens, Greece
University General Hospital of Heraklion (UnGHH)
🇬🇷Heraklion, Greece
RAMBAM Medical Center
🇮🇱Haifa, Israel
policlinico rodolico San marco
🇮🇹Catania, Italy
IRCCS Burlo Garoflo oncoematologia
🇮🇹Trieste, Italy
Universitair Medisch Centrum Groningen
🇳🇱Groningen, Netherlands
U.O.C oncoematologia pediatrica ospedale Donna Bambino
🇮🇹Verona, Italy
Children's University Hospital Košice
🇸🇰Košice, Slovakia
Kantonsspital Aarau AG Klinik für Kinder und Jugendliche
🇨🇭Aarau, Switzerland
Universitäts-Kinderspital beider Basel (UKBB)
🇨🇭Basel, Switzerland
Ospedale San Giovanni Pediatria, Emato-oncologia pediatrica
🇨🇭Bellinzona, Switzerland
CHUV - Centre Hospitalier Universitaire Vaudois
🇨🇭Lausanne, Switzerland
Ostschweizer Kinderspital Hämatologie/Onkologie Claudiusstrasse 6
🇨🇭Saint Gallen, Switzerland